Heteroaryl aminoguanidines and alkoxyguanidines and their use as protease inhibitors

ABSTRACT

Aminoguanidine and alkoxyguanidine compounds are described, including compounds of the Formula VII: ##STR1## wherein X is O or NR 9  and Het, R 1 , R 7 , R 8 , R 12  -R 15 , R a , R b , R c , Z, and n are set forth in the specification, as well as hydrates, solvates or pharmaceutically acceptable salts thereof, that inhibit proteolytic enzymes such as thrombin. Also described are methods for preparing such compounds. The compounds of the invention are potent inhibitors of proteases, especially trypsin-like serine proteases, such as chymotrypsin, trypsin, thrombin, plasmin and factor Xa. Certain of the compounds exhibit antithrombotic activity via direct, selective inhibition of thrombin. The invention includes a composition for inhibiting loss of blood platelets, inhibiting formation of blood platelet aggregates, inhibiting formation of fibrin, inhibiting thrombus formation, and inhibiting embolus formation in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier. Other uses of compounds of the invention are as anticoagulants either embedded in or physically linked to materials used in the manufacture of devices used in blood collection, blood circulation, and blood storage, such as catheters, blood dialysis machines, blood collection syringes and tubes, blood lines and stents. Additionally, the compounds can be detectably labeled and employed for in vivo imaging of thrombi.

This application claims benefit under 35 U.S.C. § 119(e) of U.S.Provisional Application No. 60/079,107, filed Mar. 23, 1998, Appl. No.60/067,324, filed Dec. 5, 1997, and Appl. No. 60/066,475, filed Nov. 26,1997, the contents of all of which are fully incorporated by referenceherein.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel compounds that function asproteolytic enzyme inhibitors, and particularly to a new class ofthrombin inhibitors.

2. Related Art

Proteases are enzymes that cleave proteins at single, specific peptidebonds. Proteases can be classified into four generic classes: serine,thiol or cysteinyl, acid or aspartyl, and metalloproteases (Cuypers etal., J. Biol. Chem. 257:7086 (1982)). Proteases are essential to avariety of biological activities, such as digestion, formation anddissolution of blood clots, reproduction and the immune reaction toforeign cells and organisms. Aberrant proteolysis is associated with anumber of disease states in man and other mammals. The human neutrophilproteases, elastase and cathepsin G, have been implicated ascontributing to disease states marked by tissue destruction. Thesedisease states include emphysema, rheumatoid arthritis, corneal ulcersand glomerular nephritis. (Barret, in Enzyme Inhibitors as Drugs,Sandler, ed., University Park Press, Baltimore, (1980)). Additionalproteases such as plasmin, C-1 esterase, C-3 convertase, urokinase,plasminogen activator, acrosin, and kallikreins play key roles in normalbiological functions of mammals. In many instances, it is beneficial todisrupt the function of one or more proteolytic enzymes in the course oftherapeutically treating a mammal.

Serine proteases include such enzymes as elastase (human leukocyte),cathepsin G, plasmin, C-1 esterase, C-3 convertase, urokinase,plasminogen activator, acrosin, chymotrypsin, trypsin, thrombin, factorXa and kallikreins.

Human leukocyte elastase is released by polymorphonuclear leukocytes atsites of inflammation and thus is a contributing cause for a number ofdisease states. Cathepsin G is another human neutrophil serine protease.Compounds with the ability to inhibit the activity of these enzymes areexpected to have an anti-inflammatory effect useful in the treatment ofgout, rheumatoid arthritis and other inflammatory diseases, and in thetreatment of emphysema. Chymotrypsin and trypsin are digestive enzymes.Inhibitors of these enzymes are useful in treating pancreatitis.Inhibitors of urokinase and plasminogen activator are useful in treatingexcessive cell growth disease states, such as benign prostatichypertrophy, prostatic carcinoma and psoriasis.

The serine protease thrombin occupies a central role in hemostasis andthrombosis, and as a multifactorial protein, induces a number of effectson platelets, endothelial cells, smooth muscle cells, leukocytes, theheart, and neurons. Activation of the coagulation cascade through eitherthe intrinsic pathway (contact activation) or the extrinsic pathway(activation by exposure of plasma to a non-endothelial surface, damageto vessel walls or tissue factor release) leads to a series ofbiochemical events that converge on thrombin. Thrombin cleavesfibrinogen ultimately leading to a hemostatic plug (clot formation),potently activates platelets through a unique proteolytic cleavage ofthe cell surface thrombin receptor (Coughlin, Seminars in Hematology31(4):270-277 (1994)), and autoamplifies its own production through afeedback mechanism. Thus, inhibitors of thrombin function havetherapeutic potential in a host of cardiovascular and non-cardiovasculardiseases.

Factor Xa is another serine protease in the coagulation pathway. FactorXa associates with factor Va and calcium on a phospholipid membranethereby forming a prothrombinase complex. This prothrombinase complexthen converts prothrombin to thrombin (Claeson, Blood Coagulation andFibrinolysis 5:411-436 (1994); Harker, Blood Coagulation andFibrinolysis 5 (Suppl 1):S47-S58 (1994)). Inhibitors of factor Xa arethought to offer an advantage over agents that directly inhibit thrombinsince direct thrombin inhibitors still permit significant new thrombingeneration (Lefkovits and Topol, Circulation 90(3):1522-1536 (1994);Harker, Blood Coagulation and Fibrinolysis 5 (Suppl 1):S47-S58 (1994)).

In vivo diagnostic imaging methods for intravascular thrombi have beenpreviously reported. These imaging methods use compounds that aredetectably labeled with radioactive or paramagnetic atoms. For example,platelets labeled with the gamma emitter, In-111, can be employed as animaging agent for detecting thrombi (Thakur, M. L. et al., Thromb Res.9:345 (1976); Powers et al., Neurology 32:938 (1982)). The thrombolyticenzyme streptokinase labeled with Tc-99m has been proposed as an imagingagent (Wong, U.S. Pat. No. 4,418,052 (1983)). The fibrin-binding domainsof Staphylococcus aureus derived protein A labeled with the gammaemitters, I-125 and I-131, have been proposed as imaging agents (Pang,U.S. Pat. No. 5,011,686 (1991)). Monoclonal antibodies havingspecificity for fibrin (in contrast to fibrinogen) and labeled withTc-99m have been proposed as imaging agents (Berger et al., U.S. Pat.No. 5,024,829 (1991); Dean et al., U.S. Pat. No. 4,980,148 (1990)). Theuse of the paramagnetic contrasting agent, gadoliniumdiethylenetriaminepentaacetic acid in magnetic resonance imaging ofpatients treated by thrombolysis for acute myocardial infarction hasbeen reported (De Roos, A. et al., Int. J. Card. Imaging 7:133 (1991)).Radiolabeled and paramagnetically labeled alpha-ketoamide derivativeshave also been proposed as thrombus imaging agents (Abelman et al., U.S.Pat. No. 5,656,600).

Edwards et al., J. Amer. Chem. Soc. 114:1854-63(1992), describespeptidyl α-ketobenzoxazoles that reversibly inhibit the serine proteaseshuman leukocyte elastase and porcine pancreatic elastase.

European Published Application 363 284 describes analogs of peptidasesubstrates in which the nitrogen atom of the scissile amide group of thesubstrate peptide has been replaced by hydrogen or a substitutedcarbonyl moiety.

Australian Published Application 86245677 also describes peptidaseinhibitors having an activated electrophilic ketone moiety such asfluoromethylene ketone or α-keto carboxyl derivatives.

Brown et al., J. Med Chem. 37:1259-1261 (1994) describes orally active,non-peptidic inhibitors of human leukocyte elastase which containtrifluoromethylketone and pyridinone moieties.

H. Mack et al., J. Enzyme Inhibition, 9:73-86 (1995) describes rigidamidinophenylalanine thrombin inhibitors which contain a pyridinonemoiety as a central core structure.

PCT International Published Application WO 97/01338 describes pyridinonecompounds having the formula: ##STR2## where

W is R¹, R¹ OCO, R¹ CO, R¹ SO₂, or (R¹)_(m) (CH₂)_(n) NH_(q) CO;

R¹ is R² (CH₂)_(n), (R²)(OR²)CH(CH₂)_(p), (R²)₂ CH(CH₂)_(n), and R²O(CH₂)_(p) ;

R² is hydrogen, optionally substituted phenyl, naphthyl, biphenyl, amono- or bicyclic heterocyclic ring, COOR⁶, C₁₋₄ linear or branchedalkyl, C₃₋₇ cycloalkyl, or C₇₋₁₂ bicyclic alkyl;

R³ is hydrogen, C₁₋₄ linear or branched alkyl C₃₋₇ cycloalkyl, ortrifluoromethyl;

A is one of: ##STR3## where

Y is hydrogen, hydroxy, or CN; and

R⁶ is hydrogen, or C₁₋₄ linear or branched alkyl.

PCT International Published Application WO97/30708 discloses pyridinonecompounds of the general formula: ##STR4## The compounds are disclosedto be useful for inhibiting thrombin and associated thromboticocclusions.

PCT Published Application WO 96/18644 describes compounds having theformula: ##STR5## wherein

Het is selected from the group consisting of ##STR6## and R₃ is selectedfrom the group consisting of: ##STR7## The compounds are described asspecific inhibitors of thrombin.

A need continues to exist for non-peptidic compounds that are potent andselective protease inhibitors, and which possess greater bioavailabilityand fewer side-effects than currently available protease inhibitors.Accordingly, new classes of potent protease inhibitors, characterized bypotent inhibitory capacity and low mammalian toxicity, are potentiallyvaluable therapeutic agents for a variety of conditions, includingtreatment of a number of mammalian proteolytic disease states.

SUMMARY OF THE INVENTION

The present invention is directed to novel aminoguanidine andalkoxyguanidine compounds having Formula VII (below). Also provided areprocesses for preparing compounds of Formula VII. The novel compounds ofthe present invention are potent inhibitors of proteases, especiallytrypsin-like serine proteases, such as chymotrypsin, trypsin, thrombin,plasmin and factor Xa. Certain of the compounds exhibit antithromboticactivity via direct, selective inhibition of thrombin, or areintermediates useful for forming compounds having antithromboticactivity. Also provided are methods of inhibiting or treating aberrantproteolysis in a mammal and methods of treating thrombosis, ischemia,stroke, restenosis or inflammation in a mammal by administering aneffective amount of a compound of Formula VII.

The invention includes a composition for inhibiting loss of bloodplatelets, inhibiting formation of blood platelet aggregates, inhibitingformation of fibrin, inhibiting thrombus formation, and inhibitingembolus formation in a mammal, comprising a compound of the invention ina pharmaceutically acceptable carrier. These compositions may optionallyinclude anticoagulants, antiplatelet agents, and thrombolytic agents.The compositions can be added to blood, blood products, or mammalianorgans in order to effect the desired inhibitions.

Also provided are methods of inhibiting or treating aberrant proteolysisin a mammal, and methods for treating myocardial infarction; unstableangina; stroke; restenosis; deep vein thrombosis; disseminatedintravascular coagulation caused by trauma, sepsis or tumor metastasis;hemodialysis; cardiopulmonary bypass surgery; adult respiratory distresssyndrome; endotoxic shock; rheumatoid arthritis; ulcerative colitis;induration; metastasis; hypercoagulability during chemotherapy;Alzheimer's disease; Down's syndrome; fibrin formation in the eye; andwound healing. Other uses of compounds of the invention are asanticoagulants either embedded in or physically linked to materials usedin the manufacture of devices used in blood collection, bloodcirculation, and blood storage, such as catheters, blood dialysismachines, blood collection syringes and tubes, blood lines and stents.

The invention also includes a method for reducing the thrombogenicity ofa surface in a mammal by attaching to the surface, either covalently ornoncovalently, a compound of the invention.

In another aspect, the present invention includes compositions which areuseful for in vivo imaging of thrombi in a mammal, comprising a compoundof the present invention which is capable of being detected outside thebody. Preferred are compositions comprising a compound of the presentinvention and a detectable label, such as a radioactive or paramagneticatom.

In another aspect, the present invention provides diagnosticcompositions which are useful for in vivo imaging of thrombi in amammal, comprising a pharmaceutically acceptable carrier and adiagnostically effective amount of a compound or composition of thepresent invention.

In another aspect, the present invention includes methods which areuseful for in vivo imaging or thrombi in a mammal.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Compounds of the present invention include compounds of Formula VII:##STR8## or a solvate, hydrate or pharmaceutically acceptable saltthereof; wherein:

R¹ is alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl,aralkyl heterocycle or heterocycloalkyl, any of which may be optionallysubstituted,

Z is --SO₂ --, --OCO--, --CO--, --NR² CO-- or a covalent bond,

where R² is hydrogen, alkyl, aralkyl, aryl, hydroxy(C₂₋₁₀)alkyl,amino(C₂₋₁₀)alkyl, monoalkylamino(C₂₋₁₀)alkyl, dialkylamino(C₂₋₁₀)alkylor carboxyalkyl;

Het is selected from the group consisting of ##STR9## where

R³, R⁴ and R⁵ are independently hydrogen, alkyl, cycloalkyl, alkenyl,alkynyl, optionally substituted aryl, optionally substituted aralkyl,optionally substituted heteroaryl, trifluoromethyl, halogen,hydroxyalkyl, cyano, nitro, carboxamido, alkoxycarbonylmethyl,carboxymethyl, --CO₂ R^(x), --CH₂ OR^(x) or --OR^(x),

where R^(x), in each instance, is independently one of hydrogen, alkylor cycloalkyl wherein said alkyl or cycloalkyl groups may optionallyhave one or more unsaturations;

R⁶ is hydrogen, alkyl, aralkyl, aryl, cyano(C₂₋₁₀)alkyl,hydroxy(C₂₋₁₀)alkyl, alkoxy(C₂₋₁₀)alkyl, mono- anddi-alkylamino(C₂₋₁₀)alkyl, or carboxyalkyl;

R⁷ is hydrogen, C₁₋₄ alkyl, or C₂₋₄ alkenyl;

R⁸ is hydrogen, alkyl, alkenyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl,monoalkylamino (C₂₋₁₀)alkyl, dialkylamino(C₂₋₁₀)alkyl or carboxyalkyl;

R¹², R¹³, R¹⁴ and R¹⁵ are independently hydrogen, alkyl, aralkyl, aryl,hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl orcarboxyalkyl;

or R¹² and R¹³ are taken together to form --(CH₂)_(y) --, where y is 2to 7, preferably 2 to 5, while R¹⁴ and R¹⁵ are defined as above;

or R¹⁴ and R¹⁵ are taken together to form --(CH₂)_(q) --, where q is 2to 7, preferably 2 to 5, while R¹² and R¹³ are defined as above;

or R¹² and R¹⁴ are taken together to form --(CH₂)_(r) --, where r is 0(a bond) or 1 to 7, preferably 0-4, while R¹³ and R¹⁵ are defined asabove;

X is oxygen or NR⁹,

where R⁹ is hydrogen, alkyl, cycloalkyl or aryl, wherein said alkyl,cycloalkyl or aryl can be optionally substituted with amino,monoalkylamino, dialkylamino, alkoxy, hydroxy, carboxy, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, aryl, heteroaryl, acylamino, cyano ortrifluoromethyl;

R^(a), R^(b) and R^(c) are independently hydrogen, alkyl, hydroxy,alkoxy, aryloxy, aralkoxy, alkoxycarbonyloxy, cyano or --O₂ R^(w), where

R^(w) is alkyl, cycloalkyl, phenyl, benzyl, ##STR10## where R^(d) andR^(c) are independently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl or phenyl,R^(f) is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl or phenyl, R^(g) ishydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl or phenyl, and R^(h) is aralkyl orC₁₋₆ alkyl;

n is from zero to 8; and

m is from zero to 6.

A preferred group of compounds falling within the scope of the presentinvention include compounds of Formula VII wherein R¹ is one of C₆₋₁₀ar(C₁₋₄) alkyl, C₆₋₁₀ aryl, C₄₋₇ cycloalkyl(C₁₋₄)alkyl, heterocycle orheterocyclo(C₁₋₄)alkyl wherein the heterocycle is a 5- to 7-memberedmono- or 9- to 10-membered bi-cyclic heterocyclic ring that can besaturated or unsaturated, which contains 1 to 3 heteroatoms selectedfrom N, O and S. Any of these R¹ groups can be optionally substituted by1-5, preferably by one, two or three of hydroxy, nitro, trifluoromethyl,halogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₆₋₁₀ aryl, C₁₋₆ alkoxy, C₆₋₁₀ar(C₁₋₆)alkoxy, C₁₋₆ aminoalkyl, C₁₋₆ aminoalkoxy, amino,mono(C₁₋₄)alkylamino, di(C₁₋₄)alkylamino, C₂₋₆ alkylcarbonylamino, C₂₋₆alkoxycarbonylamino, C₂₋₆ alkoxycarbonyl, carboxy, C₁₋₆ hydroxyalkyl,C₂₋₆ hydroxyalkoxy, (C₁₋₆)alkoxy(C₂₋₆)alkoxy, mono- and di- C₁₋₄alkylamino (C₂₋₆)alkoxy, C₂₋₁₀ mono(carboxyalkyl)amino, bis(C₂₋₁₀carboxyalkyl) amino, C₆₋₁₄ ar(C₁₋₆) alkoxycarbonyl, C₂₋₆alkynylcarbonyl, C₁₋₆ alkylsulfonyl, C₂₋₆ alkenylsulfonyl, C₂₋₆alkynylsulfonyl, C₆₋₁₀ arylsulfonyl, C₆₋₁₀ ar(C₁₋₆) alkylsulfonyl, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonamido, C₆₋₁₀ arylsulfonamido, C₆₋₁₀ar(C₁₋₆) alkylsulfonamido, amidino, guanidino, C₁₋₆ alkyliminoamino,formyliminoamino, C₂₋₆ carboxyalkoxy, C₂₋₆ carboxyalkyl,carboxyalkylamino, cyano, trifluoromethoxy, or perfluoroethoxy.

An especially preferred group of compounds include compounds of FormulaVII wherein R¹ is phenyl, benzyl, naphthyl, naphthylmethyl, pyridyl,pyridylmethyl, thienyl, thienylmethyl, quinolinyl or quinolinylmethyl,any of which is optionally substituted by one, two or three optionalsubstituents listed in the preceding paragraph, especially halo, such aschloro or fluoro, methoxy, methyl, trifluoromethyl, cyano, nitro,methylsulfonyl, amino or dimethylamino.

Useful values of R¹ include, for example, benzyl, fluorobenzyl,chlorobenzyl, iodobenzyl, dichlorobenzyl, bromobenzyl,trifluoromethylbenzyl, methylsulfonylbenzyl, di(trifluoromethyl)benzyl,methylbenzyl, t-butylbenzyl, methoxybenzyl, dimethoxybenzyl,hydroxybenzyl, carboxybenzyl, aminobenzyl, methylaminobenzyl,n-butylaminobenzyl, amidinobenzyl, guanidinobenzyl,formyliminoaminobenzyl, acetimidoylaminobenzyl, methoxycarbonylbenzyl,ethoxycarbonylbenzyl, carboxymethoxybenzyl, naphthylmethyl,hydroxynaphthylmethyl, cyclohexylmethyl, cyclopentylmethyl, phenyl,chlorophenyl, iodophenyl, dichlorophenyl, bromophenyl,trifluoromethylphenyl, methylsulfonylphenyl, di(trifluoromethyl)phenyl,methylphenyl, t-butylphenyl, methoxyphenyl, dimethoxyphenyl,hydroxyphenyl, carboxyphenyl, aminophenyl, methylaminophenyl,n-butylaminophenyl, amidinophenyl, guanidinophenyl,formyliminoaminophenyl, acetimidoylaminophenyl, methoxycarbonylphenyl,ethoxycarbonylphenyl, carboxymethoxyphenyl, naphthyl, hydroxynaphthyl,cyclohexyl, and cyclopentyl. Additional useful values include pyridyl,thienyl, isoquinolinyl, pyridylmethyl, isoquinolinylmethyl,tetrahydroquinolinyl and tetrahydroquinolinylmethyl.

More preferred values of R¹ include phenyl, 2-chlorophenyl,3-chlorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl,4-methoxyphenyl, 4-methylphenyl, 2-trifluoromethylphenyl,4-trifluoromethylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 3,5-dichlorophenyl,2-methylphenyl, 3-methylphenyl, 4-ethylphenyl, 2-methylsulfonylphenyl,4-isopropylphenyl, 3,4-dimethoxyphenyl, 2,4,6-trimethylphenyl,2,5-dimethylphenyl, 4-vinylphenyl, 2-chloro-6-methylphenyl,3-bromo-6-methoxyphenyl, 3-chloro-2-methylphenyl,2-chloro-5-trifluoromethylphenyl, 2,4-dichlorophenyl,2-butoxy-5-(1,1-dimethylpropyl)phenyl, 3-nitrophenyl,4-chloro-3-nitrophenyl, 4-methylcarbonylaminophenyl, 4-tert-butylphenyl,3-cyanophenyl, 4-methylsulfonylphenyl, pentafluorophenyl,2,5-dichlorophenyl, 2,4-dimethoxyphenyl, 2-methyl-5-nitrophenyl,3-chloro-2-cyanophenoxy)phenyl, 2-chloro-4-fluorophenyl,3-chloro-6-methoxyphenyl, 2-methoxy-5-methylphenyl, 4-phenylphenyl,2-propylbutyl, 5-chloro-2-methoxyphenyl, 2-cyanophenyl,2-(N-hydroxy)aminophenyl, 2-(4-biphenylmethoxy)phenyl,2-(3-biphenylmethoxy)phenyl, benzyl, 2-(phenylsulfonyl)phenyl,2,4-bis(methylsulfonyl)phenyl, 2-chloro4-methylsulfonylphenyl, benzyl,3-chlorobenzyl, 3-trifluoromethylbenzyl, 2-trifluoromethylbenzyl,2-iodobenzyl, 2-chlorobenzyl, 2-bromobenzyl, 3-fluorobenzyl,4-chlorobenzyl, 2-chloro-6-fluorobenzyl, 2-fluorobenzyl,2,3-dichlorobenzyl, 3,4-difluorobenzyl, 2,4-dichlorobenzyl,2,5-dichlorobenzyl, 3,4-dichlorobenzyl, 2-methylbenzyl,5-chloro-2-methoxybenzyl, 2-cyanobenzyl, 2-(4-biphenylmethoxy)benzyl,2-(3-biphenylmethoxy)benzyl, 2-(phenylsulfonyl)benzyl,2,4-bis(methylsulfonyl)benzyl, 3-methylsulfonylbenzyl,2-chloro4-methylsulfonylbenzyl, 1-naphthalenylmethyl,2-naphthalenylmethyl, and 2-naphthalenyl.

Additional preferred values of R¹ include dansyl, thien-2-yl,pyridin-2-yl, 3-methylquinolin-1-yl, 1-methylimidazol-4-yl,quinolin-5-yl, quinoline-8-yl, 6-bromonaphthalen-2-yl,6-chloronaphthalen-2-yl, 5-chlorothien-2-yl, 5-methyl-8-quinolinyl,8-quinolinylmethyl, 5-methyl-8-quinolinylmethyl,4-benzo-2,1,3-thiadiazolyl, and 5-chloro-1,3-dimethyl-4-pyrazolyl.

Preferred values of R² in Formula VII include hydrogen, C₁₋₆ alkyl,C₆₋₁₀ ar(C₁₋₆)alkyl, C₆₋₁₀ aryl, C₂₋₁₀ hydroxyalkyl, C₂₋₁₀ aminoalkyl,C₂₋₇ carboxyalkyl, mono(C₁₋₄ alkyl)amino(C₁₋₈)alkyl, and di(C₁₋₄alkyl)amino(C₁₋₈)alkyl. Suitable values of R² include hydrogen, methyl,ethyl, propyl, n-butyl, benzyl, phenylethyl, 2-hydroxyethyl,3-hydroxypropyl, 4-hydroxybutyl, 2-aminoethyl, 2-carboxymethyl,3-carboxyethyl, 4-carboxypropyl and 2-(dimethylamino)ethyl, withhydrogen being most preferred.

Preferred Het groups include ##STR11##

Preferred compounds are those where R³, R⁴ and R⁵ are independentlyhydrogen, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, especially C₆₋₁₀aryl, C₆₋₁₀ ar(C₁₋₄)alkyl, trifluoromethyl, halogen, hydroxyalkyl,cyano, nitro, carboxamido, carboxy, alkoxycarbonyl, carboxymethyl,alkoxycarbonylmethyl, or cycloalkyloxycarbonyl.

Useful values of R³, R⁴ and R⁵ include hydrogen, methyl, ethyl, propyl,chloro, bromo, trifluoromethyl, hydroxymethyl, methoxy, ethoxy,carboxamido, nitro, phenyl, cyclopropyl, hydroxy, isopropyl,methoxycarbonyl, ethoxycarbonyl and benzyl.

Preferred R³ and R⁴ groups include hydrogen, C₁₋₁₂ alkyl, and C₂₋₆alkenyl. A most preferred value of R³ and R⁴ is hydrogen.

Preferred R⁵ groups include hydrogen, halogen, C₁₋₅ alkyl, C₃₋₆ alkenyl,C₃₋₅ cycloalkyl, trifluoromethyl, and C₁₋₄ alkoxy, more preferably C₁₋₄alkyl, such as methyl, ethyl, propyl or isopropyl.

A particularly preferred Het, when R³ and R⁴ are independently selectedto be hydrogen or methyl, is ##STR12## wherein R⁵ is selected from thegroup consisting of hydrogen, methyl, ethyl, propenyl, allyl, propyl,isopropyl, butyl, R-sec-butyl, S-sec-butyl, isobutyl, 1-pentyl,R-2-pentyl, S-2-pentyl, 3-pentyl, S-1-(2-methyl)-butyl,R-2-(3-methyl)-butyl, 1-(3-methyl)-butyl, R-1-(2-methyl)-butyl,cyclopentyl, 2-pyrrolyl, 3-pyrrolyl, 1-hexyl, S-2-hexyl, R-2-hexyl,R-3-hexyl, and S-3-hexyl. A particularly preferred Het according to thisaspect has hydrogen, methyl, ethyl, propyl or isopropyl as R⁵.

Preferred values of Z include --SO₂ -- and a covalent bond.

A preferred R⁷ group is hydrogen.

Preferred compounds are those of Formula VII, where R⁸ is hydrogen, C₁₋₆alkyl or C₆₋₁₀ aryl (C₁₋₆)alkyl.

Preferred compounds when X is NR⁹ are those wherein R⁹ is hydrogen orC₁₋₆ alkyl, optionally substituted by one, two or three, preferably one,of amino, monoalkylamino, dialkylamino, alkoxy, hydroxy, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, carboalkoxy, phenyl, cyano,trifluoromethyl, acetylamino, pyridyl, thiophenyl, furyl, pyrrolyl orimidazolyl.

Suitable values of R⁹ include hydrogen, methyl, ethyl, propyl, n-butyl,benzyl, phenethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl,carboxymethyl and carboxyethyl.

Most preferred compounds are those where X is oxygen.

Preferred compounds are those of Formula VII, where R¹², R¹³, R¹⁴ andR¹⁵ are independently one of hydrogen, C₁₋₆ alkyl, C₆₋₁₀ ar(C₁₋₆)alkyl,C₆₋₁₀ aryl, C₂₋₁₀ hydroxyalkyl or C₂₋₇ carboxyalkyl. Useful values ofR¹², R¹³, R¹⁴ and R¹⁵ include hydrogen, methyl, ethyl, propyl, n-butyl,benzyl, phenylethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl,2-carboxymethyl, 3-carboxyethyl and 4-carboxypropyl. Additionalpreferred compounds are those where R¹² and R¹³ are taken together toform --(CH₂)_(y) -- where y is 2.

Preferred values of R^(a), R^(b) and R^(c) in Formula VII areindependently hydrogen, hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, cyano or --CO₂R^(w), where R^(w), in each instance, is preferably one of C₁₋₄ alkyl,C₄₋₇ cycloalkyl or benzyloxycarbonyl. Suitable values of R^(a), R^(b)and R^(c) include hydrogen, methyl, ethyl, propyl, n-butyl, hydroxy,methoxy, ethoxy, cyano, --CO₂ CH₃, --CO₂ CH₂ CH₃ and --CO₂ CH₂ CH₂ CH₃.In the most preferred embodiments, R^(a), R^(b) and R^(c) are eachhydrogen.

Also preferred at R^(a), R^(b) and R^(c) is the group --CO₂ R^(w), whereR^(w) is one of ##STR13## where R^(d) -R^(h) are defined as above. WhenR^(a), R^(b) and R^(c) are --CO₂ R², where R^(w) is one of one of thesemoieties, the resulting compounds are prodrugs that possess desirableformulation and bioavailability characteristics. A preferred value foreach of R^(d), R^(e) and R^(g) is hydrogen. R^(f) is methyl, andpreferred values for R^(h) include benzyl and tert-butyl.

Preferred values of n in Formula VII include from zero to 6, morepreferably from zero to 4, and most preferably zero, 1 or 2.

Preferred values of m are from zero to 4, most preferably zero, 1 or 2.

In the most preferred compounds m and n are both zero.

According to a particularly preferred aspect, provided are compounds ofFormula VII wherein Z is --SO₂ --, R¹ is substituted or unsubstitutedaryl or aralkyl, Het is ##STR14## X is O, R⁸ is hydrogen, C₁₋₆ alkyl orC₆₋₁₀ aryl (C₁₋₆)alkyl and R^(a), R^(b) and R^(c) are all hydrogen. Avery preferred aspect is directed to such compounds where R¹ issubstituted or unsubstituted benzyl or phenyl, X is O, and R⁸ ishydrogen, C₁₋₆ alkyl, or C₆₋₁₀ aryl(C₁₋₆)alkyl, and R^(a), R^(b) andR^(c) are all hydrogen.

A preferred group of compounds has Formula VIII: ##STR15## or a solvate,hydrate of pharmaceutically acceptable salt thereof; wherein

Z' is --OCO--, --CO--, --SO₂ --, --NHCO--, or a covalent bond;

R²¹ is R²² (CH₂)_(k), where k is 0-4, (R²²)(OR²²)CH(CH₂)_(p), where p is1-4, (R²²)₂ CH(CH₂)_(k), where k is 0-4 and R²² can be the same ordifferent, and wherein (R²²)₂ can also be a ring substituent on CHrepresented by C₃₋₇ cycloalkyl, C₇₋₁₂ bicyclic alkyl or a 5- to 7-membered mono-, or 9- to 10-membered bicyclic heterocyclic ring whichcan be saturated or unsaturated, and which contains from one to threeheteroatoms selected from the group consisting of N, O and S, and R²²O(CH₂)_(p), wherein p is 1-4;

R²² is hydrogen; phenyl, unsubstituted or substituted with one or moreof C₁₋₄ alkyl, C₁₋₄ alkoxy, halogen, trifluoromethyl, hydroxy, COOH, orCONH₂ ; naphthyl; biphenyl; a 5- to 7-membered mono- or a 9- to10-membered bicyclic heterocyclic ring which can be saturated or##STR16## where R^(d) and R^(e) are independently hydrogen, C₁₋₆ alkyl,C₂₋₆ alkenyl or phenyl, R^(f) is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl orphenyl, R^(g) is hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl or phenyl, and R^(h)is aralkyl or C₁₋₆ alkyl;

R³², R³³, R³⁴ and R³⁵ are independently one of hydrogen, C₁₋₆ alkylC₂₋₁₀ carboxyalkyl or C₂₋₁₀ hydroxyalkyl, or R³² and R³³ are takentogether to form --(CH₂)_(y) --, where y is 2 to 5, while R³⁴ and R³⁵are defined as above; or R³⁴ and R³⁵ are taken together to form--(CH₂)_(q) --, where q is 2 to 5, while R³² and R³³ are defined asabove; or R³² and R³⁴ are taken together to form --(CH₂)_(r) --, where ris 0 (a bond) or 1-4, while R³³ and R³⁵ are defined as above;

R²⁸ is hydrogen, C₁₋₄ alkyl or C₆₋₁₀ aryl(C₁₋₄)alkyl; X' is O;

n is from zero to 4; and

m is zero to 2.

A useful class of compounds is the embodiment wherein Z' is a covalentbond or --SO₂ --. A further useful subclass of compounds is theembodiment wherein R²¹ is R²² (CH)_(k), (R²²)₂ CH(CH₂)_(k), phenyl, or(phenyl)₂ --CH.

Another useful class of compounds is the embodiment wherein R²⁵ is C₁₋₄alkyl and particularly wherein R²⁵ is methyl, ethyl, propyl orisopropyl.

Another useful class of compounds it's the embodiment wherein R²⁸ ishydrogen or C₁₋₄ alkyl, and X' is O.

Exemplary structures of compounds within the scope of the inventioninclude the following: ##STR17## as well as pharmaceutically acceptablesalts thereof, for example the hydrochloride and acetate salts thereof.

Examples of novel individual compounds falling within the scope of thepresent invention include:

3-Benzylsulfonylamino-6-methyl-1-[(3-guanidinooxypropyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-Benzylsulfonylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-Benzylsulfonylamino-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(Benzyloxycarbonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(Benzylsulfonyl)amino-methyl-1-[(1-(1-guanidinooxymethyl)cyclopropyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(Benzylsulfonyl)amino-6-methyl-1-[(4-guanidinooxy)piperidinylcarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(3-Chlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(3-Trifluoromethylbenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(2-Trifluoromethylbenzyl)sulfonylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(2-Iodobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(2-Chlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(2-Bromobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(3-Fluorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(4-Chlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-((2-Chloro-6-fluoro)benzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(2-Fluorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(2,3-Dichlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(3,4-Difluorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(2,4-Dichlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(2,5-Dichlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(3,4-Dichlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(1-naphthalenylmethylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(2-naphthalenylmethylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(2-Methylbenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(3-Chlorobenzylsulfonyl)-N-methylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(3,4-Dichlorobenzylsulfonyl)-N-methylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(2-Chlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(4-Chlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(Phenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(3-Chlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(2-Methylsulfonylphenyl)sulfonylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(2-Naphthalenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(4-Bromophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(4-Fluorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(4-Iodophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(4-Methoxyphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(4-Methylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(3-Trifluoromethylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(3,4-dichlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(3-Chloro-4-fluorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(4-Isopropylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(3-Fluorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(3,5-Dichlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(3,4-Dimethoxyphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(2-Thienylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(1-Naphthalenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(2,4,6-Trimethylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(2-Methylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(2,5-Dimethylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(2-Fluorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(2-Chloro-6-methylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxypropyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(3-Bromo-6-methoxyphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(3-Chloro-2-methylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(2-Chloro-5-trifluoromethylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(2,4-Dichlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(4-Vinylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(2-Butoxy-5-(1,1-dimethylpropyl)phenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate;

3-(3-Nitrophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(4-Chloro-3-nitrophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(4-Methylcarbonylaminophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(4-tert-Butylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(4-Trifluoromethylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(3-Cyanophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(4-Methylsulfonylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-Dansylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate:

3-(Pentafluorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(2,5-Dichlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(2-Nitrophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-Di(4-nitrophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(2,5-Dimethoxyphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(4-Propylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(2-Methyl-5-nitrophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(2-Trifluoromethylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(2,3-Dichlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(2-Trifluoromethoxyphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(4-(3-Chloro-2-cyanophenoxy)phenylsulfonyl)amino-6-methyl-1-[(2-guanidino-oxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate;

3-(2-Chloro-4-fluorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(3-Chloro-6-methoxyphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(2-Methoxy-5-methylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(4-Phenylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(5-Chlorothiophene-2-sulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(6-Chloronaphthalene-2-sulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(6-Bromonaphthalene-2-sulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(3-Bromophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(Quinoline-8-sulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(Quinoline-5-sulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(1-Methylimidazole-4-sulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(3-Methylquinoline-8-sulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(2-Pyridinylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(3-Pyridinylsulfonyl)amino-6-methyl-1-[(2-guanidinooxypropyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(4-Ethylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)-N-methylaminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(3-Methylphenylsulfonyl)amino-6-isopropyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(3-Methylphenylsulfonyl)amino-6-ethyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(3-Methylphenylsulfonyl)amino-6-propyl-1-{2-(guanidinyloxyethyl)aminocarbonylmethyl}-2-pyridinone-trifluoroacetate;

3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-N"-methylguanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonehydrochloride;

3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-N"-ethylguanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonehydrochloride;

3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-N"-benzylguanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonehydrochloride;

3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-N"-butylguanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonehydrochloride;

3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-N-methylguanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(Benzylsulfonyl)amino-6-methyl-1-[(2-N-methylguanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate;

3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-(N-methoxycarbonyl)guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;

3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-(N,N',N"-triethoxycarbonyl)guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;

3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-(N,N'-diethoxycarbonyl)guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;and

3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-(-1-ethoxycarbonyl)guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone.

It is also to be understood that the present invention is considered toinclude stereoisomers as well as optical isomers, e.g. mixtures ofenantiomers as well as individual enantiomers and diastereomers, whicharise as a consequence of structural asymmetry in selected compounds ofthe present series.

The compounds of Formula VII may also be solvated, especially hydrated.Hydration may occur during manufacturing of the compounds orcompositions comprising the compounds, or the hydration may occur overtime due to the hygroscopic nature of the compounds.

Certain compounds within the scope of Formula VII are derivativesreferred to as prodrugs. The expression "prodrug" denotes a derivativeof a known direct acting drug, which derivative has enhanced deliverycharacteristics and therapeutic value as compared to the drug, and istransformed into the active drug by an enzymatic or chemical process.Useful prodrugs are those where R^(a), R^(b) and/or R^(c) are --CO₂R^(w), where R^(w) is defined above, See, U.S. Pat. No. 5,466,811 andSaulnier et al., Bioorg. Med. Chem. Lett. 4:1985-1990 (1994).

When any variable occurs more than one time in any constituent or inFormula VII, its definition on each occurrence is independent of itsdefinition at every other occurrence. Also, combinations of substituentsand/or variables are permissible only if such combinations result instable compounds.

In another aspect, the present invention includes compositions which areuseful for in vivo imaging of thrombi in a mammal, comprising a compoundof the present invention which is capable of being detected outside thebody. Preferred are compositions comprising a compound of the presentinvention and a detectable label, such as a radioactive or paramagneticatom.

In another aspect, the present invention includes methods which areuseful for in vivo imaging or thrombi in a mammal.

According to a preferred aspect, useful compounds are those wherein theR¹ substituent is substituted with a detectable label, such as aradioactive iodine atom, such as I-125, I-131 or I-123. In this aspect,R¹ is preferably phenyl, having a para I-123, para I-125 or para I-131substitution, or benzyl, having a meta I-123, meta I-125 or meta I-131substitution.

The detectable label can also be a radioactive or paramagnetic chelatein which a suitable ligand (L) is attached to an R¹ substituent, eitherdirectly or via a divalent linking group A". Alternatively, the group--A"--L substitutes for the groups --Z--R¹ in Formula VII. By suitableligand is meant an organic moiety that is capable of chelating aradioactive or paramagnetic metal ion.

In these compounds, the divalent linking group A" includes groups thatare capable of covalently bonding with a free amino group and thechelating means. For example, A" may be --C(═S)--, --C(═O)--,--C(═NH)--(CH₂)₆ --C(═NH)--, --(═O)--(CH₂)₆ --C(═O)--, ##STR18## and thelike.

Also, in the compounds represented by Formula VII, the chelating ligand,L, includes groups capable of covalently bonding to or noncovalentlybinding to either a radioactive or paramagnetic atom. The chelatingmeans including those which are customarily used for complexingradioactive or paramagnetic atoms. These include chelating meanscontaining 3 to 12, preferably 3 to 8, methylene phosphonic acid groups,methylene carbohydroxamic acid groups, carboxyethylidene groups, orespecially carboxymethylene groups, which are bonded to a nitrogen atom.If only one or two of the acid groups are bonded to a nitrogen atom,then that nitrogen is bonded to another nitrogen atom having such groupsby an optionally substituted ethylene groups or by up to four separatedethylene units separated by a nitrogen or oxygen or sulfur atom.Preferred as a completing means isdiethylenetrimine-N,N,N',N",N"-pentaacetic acid (DTPA). DTPA is wellknown in the art as a chelating means for the radioactive atomindium-111 (In-111), technetium-99m (Tc-99m), and the paramagnetic atomgadolinium (Gd). Khaw, et al., Science 209:295 (1980); Paik C. H. etal., U.S. Pat. No. 4,652,440 (1987); Gries, H. et al., U.S. Pat. No.4,957,939 (1990). A preferred chelating ligand, L, is1-(p-aminobenzyl)-diethylenetriaminepentaacetic acid. Also included aschelating means are compounds which contain sulfhydryl or aminemoieties, the total of which in any combination is at least four. Thesesulfhydryl or amine moieties are separated from each other by at leasttwo atoms which can be either carbon, nitrogen, oxygen, or sulfur.Especially preferred for chelating means, L, is metallothionein which iswell known in the art as a chelating means for Tc-99m.

The term "alkyl" as employed herein by itself or as part of anothergroup refers to both straight and branched chain radicals of up to 12carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl,isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl.

The term "alkenyl" is used herein to mean a straight or branched chainradical of 2-20 carbon atoms, unless the chain length is limitedthereto, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. Preferably, thealkenyl chain is 2 to 10 carbon atoms in length, more preferably, 2 to 8carbon atoms in length most preferably from 2 to 4 carbon atoms inlength.

The term "alkynyl" is used herein to mean a straight or branched chainradical of 2-20 carbon atoms, unless the chain length is limitedthereto, wherein there is at least one triple bond between two of thecarbon atoms in the chain, including, but not limited to, acetylene,1-propylene, 2-propylene, and the like. Preferably, the alkynyl chain is2 to 10 carbon atoms in length, more preferably, 2 to 8 carbon atoms inlength, most preferably from 2 to 4 carbon atoms in length.

In all instances herein where there is an alkenyl or alkynyl moiety as asubstituent group, the unsaturated linkage, i.e., the vinylene oracetylene linkage is preferably not directly attached to a nitrogen,oxygen or sulfur moiety.

The term "alkoxy" is used herein to mean a straight or branched chainradical of 1 to 20 carbon atoms, unless the chain length is limitedthereto, bonded to an oxygen atom, including, but not limited to,methoxy, ethoxy, n-propoxy, isopropoxy, and the like. Preferably thealkoxy chain is 1 to 10 carbon atoms in length, more preferably 1 to 8carbon atoms in length.

The term "aryl" as employed herein by itself or as part of another grouprefers to monocyclic or bicyclic aromatic groups containing from 6 to 12carbons in the ring portion, preferably 6-10 carbons in the ringportion, such as phenyl, naphthyl or tetrahydronaphthyl.

The term "heteroaryl" as employed herein refers to groups having 5 to 14ring atoms; 6, 10 or 14π electrons shared in a cyclic array; andcontaining carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfurheteroatoms (where examples of heteroaryl groups are: thienyl,benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, pyranyl,isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl, phenoxathiinyl,2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl,pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl,indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl,phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl,4αH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl,perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl,isoxazolyl, furazanyl and phenoxazinyl groups).

The term "aralkyl" or "arylalkyl" as employed herein by itself or aspart of another group refers to C₁₋₆ alkyl groups as discussed abovehaving an aryl substituent such as benzyl, phenylethyl or2-naphthylmethyl.

The term "cycloalkyl" as employed herein by itself or as part of anothergroup refers to cycloalkyl groups containing 3 to 9 carbon atoms.Typical examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl and cyclononyl.

The term "C₇₋₁₂ bicyclic alkyl" is intended to includebicyclo[2.2.1]heptyl (norbornyl), bicyclo[2.2.2]octyl,1,1,3-trimethylbicyclo[2.2.1]heptyl (bornyl), and the like.

The terms "alkoxy" refers to any of the above alkyl groups linked to anoxygen atom.

The term "halogen" or "halo" as employed herein by itself or as part ofanother group refers to chlorine, bromine, fluorine or iodine withchlorine being preferred.

The term "monoalkylamine" as employed herein by itself or as part ofanother group refers to an amino group which is substituted with onealkyl group having from 1 to 6 carbon atoms.

The term "dialkylamine" as employed herein by itself or as part ofanother group refers to an amino group which is substituted with twoalkyl groups, each having from 1 to 6 carbon atoms.

The term "hydroxyalkyl" as employed herein refers to any of the abovealkyl groups substituted by one or more hydroxyl moieties.

The term "carboxyalkyl" as employed herein refers to any of the abovealkyl groups substituted by one or more carboxylic acid moieties.

The term "heterocycle" or "heterocyclic ring", as used herein exceptwhere noted, represents a stable 5- to 7-membered mono- or bicyclic orstable 7- to 10-membered bicyclic heterocyclic ring system any ring ofwhich may be saturated or unsaturated, and which consists of carbonatoms and from one to three heteroatoms selected from the groupconsisting of N, O and S, and wherein the nitrogen and sulfurheteroatoms may optionally be oxidized, and the nitrogen heteroatom mayoptionally be quaternized, and including any bicyclic group in which anyof the above-defined heterocyclic rings is fused to a benzene ring.Especially useful are rings containing one oxygen or sulfur, one tothree nitrogen atoms, or one oxygen or sulfur combined with one or twonitrogen atoms. The heterocyclic ring may be attached at any heteroatomor carbon atom which results in the creation of a stable structure.Examples of such heterocyclic groups include piperidinyl, piperazinyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl,azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl,pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl,isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl,quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl,benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl,furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, andoxadiazolyl. Morpholino is the same as morpholinyl.

The term "heteroatom" is used herein to mean an oxygen atom ("O"), asulfur atom ("S") or a nitrogen atom ("N"). It will be recognized thatwhen the heteroatom is nitrogen, it may form an NR^(a) R^(b) moiety,wherein R^(a) and R^(b) are, independently from one another, hydrogen orC₁ to C₈ alkyl, or together with the nitrogen to which they are bound,form a saturated or unsaturated 5-, 6-, or 7-membered ring.

Schemes 1 and 2 outline the synthesis of compounds of the presentinvention where R¹ --Z-- is R¹ --SO₂ --. ##STR19## where R¹² -R¹⁵,R^(a), R^(b), R^(c), n and m are as defined above.

In Scheme 1, an aminoalcohol 1 is protected using a standard aminoprotecting group such as benzyloxycarbonyl (Cbz) to give compound 2. Theprotected aminoalcohol 2 is coupled to N-hydroxyphthalimide using aMitsunobu coupling procedure (Mitsunobu, O., Synthesis, 1 (1981)) toprovide compound 3. Preferred coupling conditions include using asolvent, such as tetrahydrofuran or methylene chloride, and a dialkylazodicarboxylate, such as diethyl azodicarboxylate. Unveiling of thephthalimide protecting group to form alkoxyamine 4 is accomplished usingstandard conditions well known in the art (Greene, T. W., Wuts, P. G.W., Protecting Groups in Organic Synthesis, 2nd edition, John Wiley andSons, Inc. New York, (1991)), such as methylamine or hydrazine, in anappropriate solvent, such as ethanol or iso-propanol. Guanidinylation ofthe resulting alkoxyamine 4 to 5 is accomplished using substitutedguanidinylating reagents such asN,N'-bis(tert-butoxycarbonyl)-S-methylthiourea (Bergeron, R. J. andMcManis, J. S, J. Org. Chem., 52:1700 (1987)) or N-R^(a), N-R^(b),N-R^(c) -1H-pyrazole-1-carboxamidine (Bernatowicz, M. S., et al.,Tetrahedron Letter 34: 3389 (1993)). Deprotection of the aminoprotecting group to give intermediates 6 is accomplished using standardprocedures well known in the art (Greene, T. W., Wuts, P. G. W.,Protecting Groups in Organic Synthesis, 2nd edition, John Wiley andSons, Inc. New York, (1991)), such as palladium on carbon, in a suitablesolvent, such as chloroform in methanol or ethanol. In some cases, it isadvantageous to add an acid, such as hydrochloric acid. ##STR20## whereR¹, R³ -R⁵, R¹² -R¹⁵, R⁸, R^(a), R^(b), R^(c), n and m are definedabove.

In Scheme 2, a 2-hydroxy-pyridine carboxylic acid 7 is reacted withdiphenylphosphoryl azide (DPPA), triethylamine and benzyl alcohol in asuitable solvent, such as dioxane to afford the protected aminopyridinone 8. This is alkylated with a glycine equivalent, such astert-butyl bromoacete, using a base, such as lithiumhexamethyldisilazide, cesium carbonate, or sodium hydride, in anappropriate solvent, such as tetrahydrofuran or N,N-dimethylformamide togive compound 9. The tert-butyl group is then removed using standardconditions well known in the art (Greene, T. W., Wuts, P. G. W.,Protecting Groups in Organic Synthesis, 2nd edition, John Wiley andSons, Inc. New York, (1991)), such as HCl gas in ethyl acetate ortrifluoroacetic acid in methylene chloride, to afford acid 10. The acid10 is coupled to intermediate 6 using a standard peptide couplingreagents, such as Castro's reagent (BOP) or PyBOP, and base such asdiisopropylethylamine in a suitable solvent, such asN,N-dimethylformamide to produce compound 14. The Cbz group is removedvia hydrogenation over a catalyst such as palladium on carbon in asolvent, such as tetrahydofuran and ethanol. The amine 15 is treatedwith a sulfonyl chloride in the present of a base, such as4-methylmorpholine, in a suitable solvent, such as methylene chloride toafford compound 16.

Alternatively, the Cbz group of compound 9 is deprotected using astandard procedure such as hydrogenation in the present of a catalystsuch as palladium on carbon in an appropriate solvent, such astetrahydrofuran and ethanol. The amine 11 is reacted with a sulfonylchloride in the present of a base, such as 4-methylmorpholine, in asuitable solvent, such as methylene chloride to afford 12. Thetert-butyl group is removed using standard procedure well known in theart (Greene, T. W., Wuts, P. G. W., Protecting Groups in OrganicSynthesis, 2nd edition, John Wiley and Sons, Inc. New York, (1991)),such as HCl gas in ethyl acetate or trifluoroacetic acid in methylenechloride, to afford acid 13. The acid 13 is coupled to intermediate 6using a standard peptide coupling reagents, such as Castro's reagent(BOP) or PyBOP, and a base such as diiso-propylethylamine, in a suitablesolvent, such as N,N-dimethylformamide to give compound 16. The R^(a),R^(b) and R^(c) can be optionally removed using a standard procedure. Inthe case of R^(a) and R^(b) =tert-butoxycarbonyl (Boc) and R^(c)=hydrogen, the Boc groups can be removed by treatment with an acid, suchas trifluoroacetic acid or hydrochloric acid, in an appropriate solvent,such as methylene chloride or dioxane to provide compound 17. Compound17 can be then optionally alkylated with an alkyl halide in the presentof a base, such as sodium bicarbonate, in an appropriate solvent, suchas N,N'-dimethylformamide, to give compound 18. ##STR21## where R³, R⁵,R¹² -R¹⁵, R^(a), R^(b), R^(c), n, and m are defined above, and Ar isaryl.

In Scheme 3, diethyl ethoxymethylenemalonate 19 is treated with amidine20 in the present of base, such as sodium ethoxide, in an appropriatesolvent, such as ethanol to afford substituted pyrimidine 21. Compound21 is alkylated with a glycine equivalent, such as tert-butylbromoacetate, using a base, such as tetrabutylammonium fluoride, lithiumhexamethyldisilazide, or sodium hydride, in an appropriate solvent, suchas tetrahydrofuran or N,N-dimethylformamide to give ester 22. The esteris hydrolyzed with lithium hydroxide or sodium hydroxide in a suitablesolvent, such as methanol or ethanol, to afford acid 23. The acid isthen treated with diphenylphosphoryl azide (DPPA) in the present ofbase, such as triethylamine, to form the acyl azide which undergoes theCurtius rearrangement reaction with benzyl alcohol to form thebenzyloxycarbonyl (Cbz) protected 5-aminopyrimidione 24. The Cbz groupof compound 24 is deprotected using a standard procedure such ashydrogenation in the present of a catalyst, such as palladium on carbonin an appropriate solvent, such as tetrahydrofuran and ethanol. Theamine 25 is treated with a sulfonyl chloride in the present of a base,such as 4-methylmorpholine or triethylamine, in a suitable solvent, suchas methylene chloride to afford 26. The tert-butyl group is removedusing a standard procedure well known in the art (Greene, T. W., Wuts,P. G. W., Protecting Groups in Organic Synthesis, 2nd edition, JohnWiley and Sons, Inc. New York, (1991)), such as trifluoroacetic acid inmethylene chloride, to afford acid 27. The acid 27 is coupled tointermediate 6 using standard peptide coupling reagents, such asCastro's reagent (BOP) or PyBOP, and a base, such asdiiso-propylethylamine or triethylamine, in a suitable solvent, such asN,N-dimethylformamide to give compound 28. The R^(a), R^(b) and R^(c)can be optionally removed using a standard procedure. In the case ofR^(a) and R^(b) =tert-butoxycarbonyl (Boc) and R^(c) =hydrogen, the Bocgroups can be removed by treatment with an acid, such as trifluoroaceticacid or hydrochloric acid, in an appropriate solvent, such as methylenechloride or dioxane to provide compound 29. Compound 29 can beoptionally alkylated with an alkyl halide in the present of a base, suchas sodium bicarbonate, in a suitable solvent, such asN,N-dimethylformamide, to give compound 30. ##STR22##

Scheme 4 illustrates the preparation of compounds of the presentinvention where Z=--OCO--, --CO-- or --NR² CO--. The amine 11 is reactedwith an alkoxy carbonyl chloride, or a aryloxy carbonyl chloride, or aacyl chloride in the present of a base, such as 4-methylmorpholine ortriethylamine, in a suitable solvent, such as methylene chloride, ortreated with a isocyanate in an appropriate solvent, such as methylenechloride or toluene, to afford 31. The tert-butyl group is removed usingstandard procedures well known in the art (Greene, T. W., Wuts, P. G.W., Protecting Groups in Organic Synthesis, 2nd edition, John Wiley andSons, Inc. New York, (1991)), such as HCl gas in ethyl acetate ortrifluoroacetic acid in methylene chloride, to afford acid 32. The acid32 is coupled to intermediate 6 using a standard peptide couplingreagent, such as Castro's reagent (BOP) or PyBOP, and a base such asdiisopropylethylamine, in a suitable solvent, such asN,N-dimethylformamide, to give compound 33. Alternatively, the amine 15is treated with an alkoxy carbonyl chloride, aryloxy carbonyl chlorideor acyl chloride in the present of a base, such as 4-methylmorpholine ortriethylemine, in a suitable solvent, such as methylene chloride, ortreated with a isocyanate in an appropriate solvent, such as methylenechloride or toluene, to afford compound 33. The R^(a), R^(b) and R^(c)can be optionally removed using a standard procedure. In the case ofR^(a) and R^(b) =tert-butoxycarbonyl (Boc) and R^(c) =hydrogen, the Bocgroups can be removed by treatment with an acid, such as trifluoroaceticacid or hydrochloric acid, in an appropriate solvent, such as methylenechloride or dioxane, to provide compound 34. The compound 34 can be thenoptionally alkylated with an alkyl halide in the present of a base, suchas sodium bicarbonate, in an appropriate solvent, such asN,N-dimethylformamide, to give compound 35.

Schemes 5 and 6 provide examples of intermediates and synthetic stepsdescribed in Schemes 1 and 2 to produce compounds of Formula VII whereR¹ --Z is R¹ --SO₂ --. The variable "m" in the schemes has a value offrom 0 to 8, preferably 0 or 1. The synthetic steps in these schemes areexemplified in Examples 1 and 2 herein. ##STR23##

The pharmaceutically-acceptable salts of the compounds of Formula VII(in the form of water- or oil-soluble or dispersible products) includethe conventional non-toxic salts or the quaternary ammonium salts whichare formed, e.g., from inorganic or organic acids or bases. Examples ofsuch acid addition salts include acetate, adipate, alginate, aspartate,benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate,pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, sulfate, tartrate, thiocyanate, tosylate, andundecanoate. Base salts include ammonium salts, alkali metal salts suchas sodium and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases such asdicyclohexylamine salts, N-methyl-D-glucamine, and salts with aminoacids such as arginine, lysine, and so forth. Also, the basicnitrogen-containing groups may be quaternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride,bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl;and diamyl sulfates, long chain halides such as decyl, lauryl, myristyland stearyl chlorides, bromides and iodides, aralkyl halides like benzyland phenethyl bromides and others. Preferred acids for forming acidaddition salts include HCl and acetic acid.

The compounds of the present invention represent a novel class of potentinhibitors of metallo, acid, thiol and serine proteases. Examples of theserine proteases inhibited by compounds within the scope of theinvention include leukocyte neutrophil elastase, a proteolytic enzymeimplicated in the pathogenesis of emphysema; chymotrypsin and trypsin,digestive enzymes; pancreatic elastase, and cathepsin G, achymotrypsin-like protease also associated with leukocytes; thrombin andfactor Xa, proteolytic enzymes in the blood coagulation pathway.Inhibition of thermolysin, a metalloprotease, and pepsin, an acidprotease, are also contemplated uses of compounds of the presentinvention. The compounds of the present invention are preferablyemployed to inhibit trypsin-like proteases.

An end use application of the compounds that inhibit chymotrypsin andtrypsin is in the treatment of pancreatitis. For their end-useapplication, the potency and other biochemical parameters of theenzyme-inhibiting characteristics of the compounds of the presentinvention is readily ascertained by standard biochemical techniques wellknown in the art. Actual dose ranges for their specific end-useapplication will, of course, depend upon the nature and severity of thedisease state of the patient or animal to be treated, as determined bythe attending diagnostician. It is expected that a useful dose rangewill be about 0.01 to 10 mg per kg per day for an effective therapeuticeffect.

Compounds of the present invention that are distinguished by theirability to inhibit thrombin may be employed for a number of therapeuticpurposes. As thrombin inhibitors, compounds of the present inventioninhibit thrombin production. Therefore, these compounds are useful forthe treatment or prophylaxis of states characterized by abnormal venousor arterial thrombosis involving either thrombin production or action.These states include, but are not limited to, deep vein thrombosis;disseminated intravascular coagulopathy which occurs during septicshock, viral infections and cancer; myocardial infarction; stroke;coronary artery bypass; fibrin formation in the eye; hip replacement;and thrombus formation resulting from either thrombolytic therapy orpercutaneous transluminal coronary angioplasty (PCTA). Other usesinclude the use of said thrombin inhibitors as anticoagulants eitherembedded in or physically linked to materials used in the manufacture ofdevices used in blood collection, blood circulation, and blood storage,such as catheters, blood dialysis machines, blood collection syringesand tubes, and blood lines. The compounds of the present invention mayalso be used as an anticoagulant in extracorporeal blood circuits.

Metal stents have been shown to reduce restenosis, but are thrombogenic.A strategy for reducing the thrombogenicity of stents is to coat, embed,adsord or covalently attach a thrombin-inhibiting agent to the stentsurface. The compounds of the present invention can be employed for thispurpose. Compounds of the invention can be attached to, or embeddedwithin soluble and/or biodegradeable polymers as and thereafter coatedonto stent materials. Such polymers can include polyvinylpyrrolidone,polyhydroxy-propylmethacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted withpalmitoyl residues, polylactic acid, polyglycolic acid, copolymers ofpolylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans,polycyanoacrylates and cross linked or amphipathic block copolymers ofhydrogels. See European Application 761 251, European Application604,022, Canadian Patent 2,164,684 and PCT Published Applications WO96/11668, WO 96/32143 and WO 96/38136.

By virtue of the effects of thrombin on a host of cell types, such assmooth muscle cells, endothelial cells and neutrophils, the compounds ofthe present invention find additional use in the treatment orprophylaxis of adult respiratory distress syndrome; inflammatoryresponses; wound healing; reperfusion damage; atherosclerosis; andrestenosis following an injury such as balloon angioplasty, atherectomy,and arterial stent placement.

The compounds of the present invention may be useful in treatingneoplasia and metastasis as well as neurodegenerative diseases, such asAlzheimer's disease and Parkinson's disease.

When employed as thrombin inhibitors, the compounds of the presentinvention may be administered in an effective amount within the dosagerange of about 0.1 to about 500 mg/kg, preferably between 0.1 to 10mg/kg body weight, on a regimen in single or 2-4 divided daily doses.

When employed as inhibitors of thrombin, the compounds of the presentinvention may be used in combination with thrombolytic agents such astissue plasminogen activator, streptokinase, and urokinase.Additionally, the compounds of the present invention may be used incombination with other antithrombotic or anticoagulant drugs such as,but not limited to, fibrinogen antagonists and thromboxane receptorantagonists.

The thrombin inhibitors may also be coupled with soluble polymers astargetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the thrombininhibitors may be coupled to a class of biodegradable polymers useful inachieving controlled release of a drug, for example, polylactic acid,polyglycolic acid, copolymers of polylactic and polyglycolic acid,polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters,polyacetals, polydihydropyrans, polycyanoacrylates and cross linked oramphipathic block copolymers of hydrogels.

Human leucocyte elastase is released by polymorphonuclear leukocytes atsites of inflammation and thus is a contributing cause for a number ofdisease states. Compounds of the present invention are expected to havean anti-inflammatory effect useful in the treatment of gout, rheumatoidarthritis and other inflammatory diseases, and in the treatment ofemphysema. The leucocyte elastase inhibitory properties of compounds ofthe present invention are determined by the method described below.Cathepsin G has also been implicated in the disease states of arthritis,gout and emphysema, and in addition, glomerulonephritis and lunginfestations caused by infections in the lung. In their end-useapplication the enzyme inhibitory properties of the compounds of FormulaI is readily ascertained by standard biochemical techniques that arewell-known in the art.

The Cathepsin G inhibitory properties of compounds within the scope ofthe present invention are determined by the following method. Apreparation of partially purified human Cathepsin G is obtained by theprocedure of Baugh et al., Biochemistry 15:836 (1979). Leukocytegranules are a major source for the preparation of leukocyte elastaseand cathepsin G (chymotrypsin-like activity). Leukocytes are lysed andgranules are isolated. The leukocyte granules are extracted with 0.20 Msodium acetate, pH 4.0, and extracts are dialyzed against 0.05 M Trisbuffer, pH 8.0 containing 0.05 M NaCl overnight at 4° C. A proteinfraction precipitates during dialysis and is isolated by centrifugation.This fraction contains most of the chymotrypsin-like activity ofleukocyte granules. Specific substrates are prepared for each enzyme,namely N-Suc-Ala-Ala-Pro-Val-p-nitroanilide andSuc-Ala-Ala-Pro-Phe-p-nitroanilide. The latter is not hydrolyzed byleukocyte elastase. Enzyme preparations are assayed in 2.00 mL of 0.10 MHepes buffer, pH 7.5, containing 0.50 M NaCl, 10% dimethylsulfoxide and0.0020 M Suc-Ala-Ala-Pro-Phe-p-nitroanilide as a substrate. Hydrolysisof the p-nitroanilide substrate is monitored at 405 nm and at 25° C.

Useful dose range for the application of compounds of the presentinvention as neutrophil elastase inhibitors and as Cathepsin Ginhibitors depend upon the nature and severity of the disease state, asdetermined by the attending diagnostician, with a range of 0.01 to 10mg/kg body weight, per day, being useful for the aforementioned diseasestates.

Compounds of the present invention that inhibit urokinase or plasminogenactivator are potentially useful in treating excessive cell growthdisease state. As such compounds of the present invention may also beuseful in the treatment of benign prostatic hypertrophy and prostaticcarcinoma, the treatment of psoriasis, and as abortifacients. For theirend-use application, the potency and other biochemical parameters of theenzyme inhibiting characteristics of compounds of the present inventionare readily ascertained by standard biochemical techniques well known inthe art. Actual dose ranges for this application will depend upon thenature and severity of the disease state of the patient or animal to betreated as determined by the attending diagnostician. It is to beexpected that a general dose range will be about 0.01 to 10 mg per kgper day for an effective therapeutic effect.

Additional uses for compounds of the present invention include analysisof commercial reagent enzymes for active site concentration. Forexample, chymotrypsin is supplied as a standard reagent for use inclinical quantitation of chymotrypsin activity in pancreatic juices andfeces. Such assays are diagnostic for gastrointestinal and pancreaticdisorders. Pancreatic elastase is also supplied commercially as areagent for quantitation of α₁ -antitrypsin in plasma. Plasma α₁-antitrypsin increases in concentration during the course of severalinflammatory diseases, and α₁ -antitrypsin deficiencies are associatedwith increased incidence of lung disease. Compounds of the presentinvention can be used to enhance the accuracy and reproducibility ofthese assays by titrametric standardization of the commercial elastasesupplied as a reagent. See, U.S. Pat. No. 4,499,082.

Protease activity in certain protein extracts during purification ofparticular proteins is a recurring problem which can complicate andcompromise the results of protein isolation procedures. Certainproteases present in such extracts can be inhibited during purificationsteps by compounds of the present invention, which bind tightly tovarious proteolytic enzymes.

The pharmaceutical compositions of the invention can be administered toany animal that can experience the beneficial effects of the compoundsof the invention. Foremost among such animals are humans, although theinvention is not intended to be so limited.

The pharmaceutical compositions of the present invention can beadministered by any means that achieve their intended purpose. Forexample, administration can be by parenteral, subcutaneous, intravenous,intramuscular, intraperitoneal, transdermal, buccal, or ocular routes.Alternatively, or concurrently, administration can be by the oral route.The dosage administered will be dependent upon the age, health, andweight of the recipient, kind of concurrent treatment, if any, frequencyof treatment, and the nature of the effect desired.

In addition to the pharmacologically active compounds, the newpharmaceutical preparations can contain suitable pharmaceuticallyacceptable carriers comprising excipients and auxiliaries thatfacilitate processing of the active compounds into preparations that canbe used pharmaceutically.

The pharmaceutical preparations of the present invention aremanufactured in a manner that is, itself, known, for example, by meansof conventional mixing, granulating, dragee-making, dissolving, orlyophilizing processes. Thus, pharmaceutical preparations for oral usecan be obtained by combining the active compounds with solid excipients,optionally grinding the resulting mixture and processing the mixture ofgranules, after adding suitable auxiliaries, if desired or necessary, toobtain tablets or dragee cores.

Suitable excipients are, in particular, fillers such as saccharides, forexample, lactose or sucrose, mannitol or sorbitol, cellulosepreparations and/or calcium phosphates, for example, tricalciumphosphate or calcium hydrogen phosphate, as well as binders, such as,starch paste, using, for example, maize starch, wheat starch, ricestarch, potato starch, gelatin, tragacanth, methyl cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/orpolyvinyl pyrrolidone. If desired, disintegrating agents can be added,such as, the above-mentioned starches and also carboxymethyl-starch,cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a saltthereof, such as, sodium alginate. Auxiliaries are, above all,flow-regulating agents and lubricants, for example, silica, talc,stearic acid or salts thereof, such as, magnesium stearate or calciumstearate, and/or polyethylene glycol. Dragee cores are provided withsuitable coatings that, if desired, are resistant to gastric juices. Forthis purpose, concentrated saccharide solutions can be used, which mayoptionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethyleneglycol, and/or titanium dioxide, lacquer solutions and suitable organicsolvents or solvent mixtures. In order to produce coatings resistant togastric juices, solutions of suitable cellulose preparations, such as,acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate,are used. Dye stuffs or pigments can be added to the tablets or drageecoatings, for example, for identification or in order to characterizecombinations of active compound doses.

Other pharmaceutical preparations which can be used orally includepush-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as, glycerol or sorbitol. Thepush-fit capsules can contain the active compounds in the form ofgranules that may be mixed with fillers such as lactose, binders such asstarches, and/or lubricants such as talc or magnesium stearate and,optionally, stabilizers. In soft capsules, the active compounds arepreferably dissolved or suspended in suitable liquids, such as, fattyoils or liquid paraffin. In addition, stabilizers may be added.

Suitable formulations for parenteral administration include aqueoussolutions of the active compounds in water-soluble form, for example,water-soluble salts, alkaline solutions and cyclodextrin inclusioncomplexes. Especially preferred alkaline salts are ammonium saltsprepared, for example, with Tris, choline hydroxide, Bis-Tris propane,N-methylglucamine, or arginine. One or more modified or unmodifiedcyclodextrins can be employed to stabilize and increase the watersolubility of compounds of the present invention. Useful cyclodextrinsfor this purpose are disclosed in U.S. Pat. Nos. 4,727,064, 4,764,604,and 5,024,998.

In addition, suspensions of the active compounds as appropriate oilyinjection suspensions can be administered. Suitable lipophilic solventsor vehicles include fatty oils, for example, sesame oil, or syntheticfatty acid esters, for example, ethyl oleate or triglycerides orpolyethylene glycol-400 (the compounds are soluble in PEG-400). Aqueousinjection suspensions can contain substances that increase the viscosityof the suspension, for example, sodium carboxymethyl cellulose,sorbitol, and/or dextran. Optionally, the suspension may also containstabilizers.

Compounds of Formula VII can be labeled with radioactive iodine asdescribed below in Example 3 or by using an exchange reaction. Exchangeof hot iodine for cold iodine is well known in the art. Alternatively, aradio iodine labeled compound can be prepared from the correspondingbromo compound via a tributylstannyl intermediate. See, U.S. Pat. No.5,122,361, herein incorporated by reference.

The present invention also includes compositions which are useful for invivo imaging of thrombi in a mammal, wherein the compositions arecomprised of a compound of Formula VII complexed with a radioactiveatom.

For the compounds of Formula VII, suitable radioactive atoms includeCo-57, Cu-67, Ga-67, Ga-68, Ru-97, Tc-99m, In-111, In-113m, Hg-197,Au-198, and Pb-203. In particular, technetium-99m (Tc-99m) is an idealradioactive atom for imaging because of its nuclear properties. It is agamma emitter and has a single photon energy of 140 keV, a half-life ofabout 6 hours, and it is readily available from a Mo-99/Tc-99 generator.Rhenium-186 and -188 also have gamma emission which allows them to beimaged. Preferred compositions contain the radioactive atom, Tc-99m.

Compositions of the present invention are conveniently prepared bycompleting a compound of Formula VII with radioisotopes which aresuitable for detection externally.

The compounds of Formula VII can be labeled by any of the manytechniques known in the art to provide a composition of the presentinvention. For example, these compounds can be labeled through achelating agent such as diethylene-triaminepentaacetic acid (DTPA) ormetallothionein, both of which can be covalently attached to thecompound of Formula VII.

In general, the compositions of the present invention containingtechnetium-99m are prepared by forming an aqueous mixture oftechnetium-99m and a reducing agent and a water-soluble ligand, and thencontacting the mixture with a compound of the present inventionrepresented by Formula VII. For example, the imaging compounds of thisinvention are made by reacting technetium-99m (in an oxidized state)with the compounds of the present invention having a chelating means inthe presence of a reducing agent to form a stable complex betweentechnetium-99m in a reduced state (IV or V valence state).

One embodiment of the composition of the present invention is preparedby labeling a compound of Formula VII having a DTPA chelating means withtechnetium-99m. This may be accomplished by combining a predeterminedamount (as 5 μg to 0.5 mg) of compound of the present invention with anaqueous solution containing citrate buffer and stannous reducing agent,then adding freshly eluted sodium pertechnetate containing apredetermined level of radioactivity (as 15 mCi). After allowing anincubation of the mixture at room temperature, the reaction mixture isloaded into a shielded syringe through a sterile filter (0.2-0.22micron), then is dispensed into 0.9% saline for injection, if desired.

Another embodiment of the compositions of the present invention isprepared by labeling a compound of Formula VII having a metallothioneinchelating means with technetium-99m. This may be accomplished bycombining aqueous sodium pertechnetate-99m with aqueous stannousglucoheptonate to form a soluble complex of technetium-99m (in reducedstate) with two glucoheptonate molecules, then combining this solutionwith a compound of the Formula VII having a metallothionein attachedthereto. After incubating the mixture for a period of time and underconditions which allow for an exchange of the technetium-99m from theglucoheptonate complex to the metallothionein of the compound of FormulaVII, the technetium-labeled composition of the present invention isformed.

The source of technetium-99m should preferably be water soluble.Preferred sources are alkali and alkaline earth metal pertechnetate(TcO₄ ⁻). Technetium-99m is most preferably obtained in the form offresh sodium pertechnetate from a sterile technetium-99m generator (asfrom a conventional Mo-99/Tc-99m generator). However, any other sourceof physiologically acceptable technetium-99m may be used.

Reducing agents for use in the method are physiologically acceptable forreducing technetium-99m from its oxidized state to the IV or V valencestate or for reducing rhenium from its oxidized state. Reducing agentswhich can be used are stannous chloride, stannous fluoride, stannousglucoheptonate, stannous tartarate, and sodium dithionite. The preferredagents are stannous reducing agents, especially stannous chloride orstannous glucoheptonate. For example, stannous chloride (SnCl₂) is thereducing agent and can be used in range from 1-1,000 μg/mL. Especiallypreferred concentrations are about 30-500 μg/mL.

Citric acid complexes with technetium-99m to quickly form a stabletechnetium-99m-citrate complex. Upon contact with a compound of FormulaVII, substantially quantitative transfer of technetium-99m from itscitrate complex to the chelating means of the compound of Formula VII isachieved rapidly and under mild conditions. The amount of citric acid(as sodium citrate) can range from about 0.5 mg/ml up to the amountmaximally soluble in the medium. Preferred amounts of citric acid rangefrom 15 to 30 μg/ml.

The amount of compound of Formula VII having a chelating means can rangefrom 0.001 to about 3 mg/mL, preferably about 0.017 to about 0.15 mg/mL.Finally, technetium-99m in the form of pertechnetate can be used inamounts of preferably about 1-50 mCi. The amount of mCi per mg ofcompound of the present invention is preferably about 30-150.

Alternative compositions of the present invention include an In-111labeled compound of the present invention.

The present invention also includes compositions of the compounds of thepresent invention which are useful for in vivo imaging of thrombi in amammal, comprised of a compound represented by Formula VII complexed toa paramagnetic atom.

Preferred paramagnetic atoms are divalent or trivalent ions of elementswith an atomic number of 21 to 29, 42, 44 and 58 to 70. Suitable ionsinclude chromium(III), manganese(II), iron(III), iron(II), cobalt(II),nickel(II), copper(II), praseodymium(III), neodymium(III), samarium(III)and ytterbium(III). Because of their very strong magnetic moments,gadolinium(III), terbium(III), dysoprosium(III), holmium(III), anderbium(III) are preferred. Especially preferred for the paramagneticatom is gadolinium(III).

The compositions of the present invention may be prepared by combining acompound of Formula VII with a paramagnetic atom. For example, the metaloxide or a metal salt (for example, nitrate, chloride or sulfate) of asuitable paramagnetic atom is dissolved or suspended in a mediumcomprised of water and an alcohol, such as methyl, ethyl or isopropylalcohol. This mixture is added to a solution of an equimolar amount ofthe compound of Formula VII in a similar aqueous medium and stirred. Thereaction mixture may be heated moderately until the reaction iscompleted. Insoluble compositions formed may be isolated by filtering,while soluble compositions may be isolated by evaporation of thesolvent. If acid groups on the chelating means are still present in thecomposition of the present invention, inorganic or organic bases, andeven amino acids, may be added to convert the acidic complex into aneutral complex to facilitate isolation or purification of homogenouscomposition. Organic bases or basic amino acids may be used asneutralizing agents, as well as inorganic bases such as hydroxides,carbonates or bicarbonates of sodium, potassium or lithium.

The present invention also include diagnostic compositions which areuseful for in vivo imaging of thrombi in a mammal, comprising apharmaceutically acceptable carrier and a diagnostically effectiveamount of a radiolabeled compound of Formula VII. Compositions such asthose described above may be conveniently used in these diagnosticcompositions.

The "diagnostically effective amount" ofthe composition required as adose will depend on the route of administration, the type of mammalbeing treated, and the physical characteristics of the specific mammalunder consideration. These factors and their relationship to determiningthis dose are well known to skilled practitioners in the medialdiagnostic arts. Also, the diagnostically effective amount and method ofadministration can be tailored to achieve optimal efficacy but willdepend on such factors as weight, diet, concurrent medication and otherfactors which those skilled in the medical arts will recognize. In anyregard, the dose for imaging should be sufficient for detecting thepresence of the imaging agent at the site of a thrombus in question.Typically, radiologic imaging will require that the dose provided by thepharmaceutical composition position of the present invention be about 5to 20 μCi, preferably about 10 μCi. Magnetic resonance imaging willrequire that the dose provided be about 0.001 to 5 mmole/kg, preferablyabout 0.005 to 0.5 mmole/kg of a compound of Formula VII complexed withparamagnetic atom. In either case, it is known in the art that theactual dose will depend on the location of the thrombus.

"Pharmaceutically acceptable carriers" for in vivo use are well known inthe pharmaceutical art, and are described, for example, in Remington'sPharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985).

The present invention also encompasses diagnostic compositions preparedfor storage or administration. These would additionally containpreservatives, stabilizers and dyes. For example, sodium benzoate,sorbic acid and esters of p-hydroxybenzoic acid may be added aspreservatives. Id. At 1449. In addition, antioxidants and suspendingagents may be used.

The in vivo imaging methods of the present invention also offer severaladvantages over previous imaging techniques for the detection ormonitoring of the presence, size, regression or increase of a thrombus.In particular, the present invention provides compounds, compositionsand diagnostic compositions have been designed to bind extremely tightlyto the thrombin associated with a thrombus and thereby reduce"background" due to circulating radioactivity or paramagnetism arisingfrom unbound imaging agent. Furthermore, in vivo imaging byintracoronary injection of the compounds, compositions or diagnosticcompositions of the present invention, is expected to be almostinstantaneous since these imaging agents would saturate the thrombinbound to the thrombus immediately.

Accordingly, the present invention also includes methods for in vivoimaging of a thrombus in a mammal, comprising the steps of: (1)administering to a mammal a diagnostically acceptable amount of acompound, composition, or diagnostic composition of the presentinvention and (2) detecting a thrombus in a blood vessel.

In employing the compounds, compositions or diagnostic compositions invivo by this method, "administering" is accomplished parenterally, ineither a systemic or local targeted manner. Systemic administration isaccomplished by injecting the compounds, compositions by diagnosticcompositions of the present invention into a convenient and accessiblevein or artery. This includes but is not limited to administration bythe ankecubutal vein. Local targeted administration is accomplished byinjecting the compounds, compositions or diagnostic compositions of thepresent invention proximal in flow to a vein or artery suspected tocontain thrombi distal to the injection site. This includes but is notlimited to direct injection into the coronary arterial vasculature toimage coronary thrombi, into the carotid artery to image thrombi in thecerebral vasculature, or into a pedal vein to image deep vein thrombosisof the leg.

Also, the manner of delivery of a composition of the present inventionto the site of a thrombus is considered within the scope of the term"administering". For example, a compound represented by Formula VIIhaving a chelating means attached thereto may be injected into themammal, followed at a later time by the radioactive atom thereby formingin vivo at the site of the thrombus the composition comprising thecompound of formula complexed to radioactive atom. Alternatively, acomposition comprising the compound of formula complexed to radioactiveatom may be injected into the mammal.

The detecting of a thrombus by imaging is made possible by the presenceof radioactive or paramagnetic atoms localized at such thrombus.

The radioactive atoms associated with the compositions and diagnosticcompositions of the present invention are preferably imaged using aradiation detection means capable of detecting gamma radiation, such asa gamma camera or the like. Typically, radiation imaging cameras employa conversion medium (wherein the high energy gamma ray is absorbed,displacing an electron which emits a photon upon its return to theorbital state), photoelectric detectors arranged in a spatial detectionchamber (to determine the position of the emitted photons), andcircuitry to analyze the photons detected in the chamber and produce animage.

The paramagnetic atoms associated with the compositions and diagnosticcompositions of the present invention are detected in magnetic resonanceimaging (MRI) systems. In such systems, a strong magnetic field is usedto align the nuclear spin vectors of the atoms in a patient's body. Thefield is disturbed by the presence of paramagnetic atoms localized at athrombus and an image of the patient is read as the nuclei return totheir equilibrium alignments.

The following examples are illustrative, but not limiting, of the methodand compositions of the present invention. Other suitable modificationsand adaptations of the variety of conditions and parameters normallyencountered and obvious to those skilled in the art are within thespirit and scope of the invention.

Example 13-Benzylsulfonylamino-6-methyl-1-[(3-guanidinooxypropyl)aminocarbonylmethyl]-2-pyridinonetrifluorocaetate ##STR24## 1.3-Benzyloxycarbonylamino-6-methyl-2-pyridinone

Diphenyiphosphoryl azide (11.9 mL, 55 mmol) was added to a solution of2-hydroxy-6-methylpyridine-3-carboxylic acid (7.65 g, 50 mmol) andtriethylamine (7.7 mL, 55 mmol) in dry dioxane (100 mL) and theresulting solution was heated to reflux. After 16 h more triethylamine(7.7 mL, 55 mmol) and benzyl alcohol (5.7 mL, 50 mmol) were added andthe solution was refluxed for a further 24 h. The reaction mixture wasconcentrated in vacuo and the residue was partitioned between methylenechloride (200 mL) and brine (100 mL), acidified to pH 1 with 10% HCl.The organic layer was washed with saturated NaHCO₃ (2×100 mL), brine(100 mL), dried over Na₂ SO₄ and filtered. After evaporating the solventin vacuo, methanol (100 mL) and hexane (20 mL) were added to theresidue, the solid was collected, washed with methanol (50 mL) and driedto give the title compound as a white solid (7.2 g, 56%). ¹ H-NMR (300MHz, CDCl₃) δ12.82 (s, 1H), 8.06 (d, J=7.0 Hz, 1H), 7.69 (s, 1H), 7.42(m, 5H), 6.09 (d, J=7.5 Hz, 1H), 5.22 (s, 2H), 2.32 (s, 3H).

2.3-Benzyloxycarbonylamino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone

tert-Butyl bromoacetate (3.9 g, 20 mmol) was added to a stirredsuspension of 3-benzyloxycarbonylamino-6-methyl-2-pyridinone (5.15 g, 20mmol), as prepared in the preceding step, and Cs₂ CO₃ (6.5 g, 20 mmol)in N,N-dimethylformamide (50 mL) and stirred at 40° C. overnight. Thesolid was removed by filtration and the filtrate concentrated under highvacuum. The residue was dissolved in ethyl acetate (150 mL), washed withwater (2×50 mL), brine (50 mL), dried over Na₂ SO₄ and concentrated invacuo. After evaporating the solvent in vacuo, the residue was purifiedby flash column chromatography (25% ethyl acetate in hexane) to give thetitle compound as a white crystalline solid (4.2 g, 56%). ¹ H-NMR (300MHz, CDCl₃) δ7.95 (d, J=7.3 Hz, 1H), 7.76 (s, 1H), 7.37 (m, 5H), 6.09(d, J=7.6 Hz, 1H), 5.19 (s, 2H), 4.75 (s, 2H), 2.32 (s, 3H), 1.47 (s,9H).

3. 3-Amino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone

A mixture of3-benzyloxycarbonylamino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone(4.1 g, 11 mmol), as prepared in the preceding step, and 10% Pd/C (400mg) in ethanol (100 mL) was hydrogenated under hydrogen (balloon) for1.5 h. The catalyst was removed by filtration through Celite and thefiltrate concentrated to give the title compound as white solid (2.55 g,97%). ¹ H-NMR (300 MHz, CDCl₃) δ6.49 (d, J=7.3 Hz, 1H), 5.92 (d, J=7.3Hz, 1H), 4.75 (s, 2H), 2.19 (s, 3H), 1.47 (s, 9H).

4.3-Benzylsulfonylamino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone

To a solution of3-amino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone (960 mg, 4.0mmol), as prepared in the preceding step, and N-methylmorpholine (840μL, 8.0 mmol) in methylene chloride (40 mL) was added α-toluenesulfonylchloride (765 mg, 4.0 mmol) at 0° C. The reaction mixture was stirred at0° C. for 1 h. Additional methylene chloride (50 mL) was added. Theresulting methylene chloride solution was washed with saturated NaHCO₃(2×50 mL), 10% citric acid (3×50 mL) and brine (50 mL), and dried overNa₂ SO₄. The solvent was concentrated to give a solid which was washedwith ethyl acetate/hexane (1:2, 60 mL) to give the title compound as awhite solid (1.4 g, 89%). 1H-NMR (300 MHz, CDCl₃) δ7.35 (d, J=7.5 Hz,1H), 7.31 (m, 5H), 7.20 (s, 1H), 6.02 (d, J=7.4 Hz, 1H), 4.75 (s, 2H),4.31 (s, 2H), 2.27 (s, 3H), 1.51 (s, 9H).

5. 3-Benzylsulfonylamino-6-methyl-1-carboxymethyl-2-pyridinone

HCl gas was bubbled through a stirred suspension of3-benzylsulfonylamino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone(1.4 g, 3.57 mmol), as prepared in the preceding step, in ethyl acetate(15 mL) at 0° C. until a solution was formed. After 2 h at roomtemperature, a thick suspension was formed. The mixture was degassedwith nitrogen and filtered to give the title compound a white solid (1.1g, 92%). ¹ H-NMR (300 MHz, CDCl₃) δ8.67 (s, 1H), 7.34 (m, 5H), 7.12 (d,J=7.5 Hz, 1H), 6.10 (d, J=7.6 Hz, 1H), 4.78 (s, 2H), 4.51 (s, 2H), 2.26(s, 3H).

6. 3-(Benzyloxycarbonylamino)-1-propanol

To a solution of 3-amino-1-propanol (3.75 g, 50 mmol) in methylenechloride (40 mL) was slowly added benzyl chloroformate (3.4 g, 20 mmol)in methylene chloride (10 mL) at 0° C. and the mixture was stirred at 0°C. for 3 h. Additional methylene chloride (50 mL) was added, thesolution washed with 10% citric acid (3×50 mL) and brine (50 mL), anddried over Na₂ SO₄. After evaporating the solvent in vacuo, the residuewas purified by filtration through silica gel (1:1 ethyl acetate:hexane)to give the title compound as a white solid (4.05 g, 97%). ¹ H-NMR (300MHz, CDCl₃) δ7.34 (m, 5H), 5.17 (br s, 1H), 5.10 (s, 2H), 3.66 (t, J=5.8Hz, 2H), 3.33 (t, J=6.1 Hz, 2H), 2.63 (br s, 1H), 1.69 (pentet, J=6.1Hz, 2H).

7. N-[3-(Benzyloxycarbonylamino)-1-propoxy]phthalimide

To a solution of 3-(benzyloxycarbonylamino)-1-propanol (4.0 g, 19 mmol),as prepared in the preceding step, N-hydroxyphthalimide (3.26 g, 20mmol) and triphenylphosphine (5.25 g, 20 mmol) in tetrahydrofuran (80mL) was added diethyl azodicaroxylate (3.5 g, 20 mmol). The reactionmixture was stirred at room temperature overnight. Ethyl acetate (200mL) was added, the solution washed with saturated NaHCO₃ (2×100 mL) andbrine (100 mL), and dried over Na₂ SO₄. After evaporating the solvent,the residue was purified by flash column chromatography (methylenechloride to 4% ethyl acetate in methylene chloride) to give the titlecompound as a white solid (6.85 g, 100%). ¹ H-NMR (300MHz, CDCl₃) δ7.83(m, 2H), 7.77 (m, 2H), 7.36 (m, 5H), 5.67 (br s, 1H), 5.12 (s, 2H), 4.28(t, J=5.8 Hz, 2H), 3.51 (q, J=6.1 Hz, 2H), 1.99 (pentet, J=6.0 Hz, 2H).

8. 3-(Benzyloxycarbonylamino)-1-propoxyamine

To a solution of N-[3-(benzyloxycarbonylamino)-1-propoxy]phthalimide(1.42 g, 4.0 mmol), as prepared in the preceding step, in ethanol (20mL) and tetrahydrofuran (20 mL) was added 40% methylamine (2 mL, 25mmol). The solution was stirred at room temperature for 1 h. The solventwas evaporated and the residue passed through silica gel (3:1 ethylacetate:hexane to ethyl acetate) to give the title compound as a whitesolid (870 mg, 97%). ¹ H-NMR (300 MHz, CDCl₃) δ7.36 (m, 5H), 5.38 (br s,2H), 5.09 (s, 2H), 5.08 (br s, 1H), 3.73 (t, J=5.9 Hz, 2H), 3.29 (q,J=6.2 Hz, 2H), 1.79 (pentet, J=6.2 Hz, 2H).

9.[N,N'-Di(tert-butoxycarbonyl)]3-(benzyloxycarbonylamino)-1-propoxyguanidine

To a solution of 3-(benzyloxycarbonylamino)-1-propoxyamine (860 mg, 3.84mmol), as prepared in the preceding step, in N,N-dimethylformamide (20mL) was added [N,N'-di(tert-butoxycarbonyl)]amidinopyrazole (1.25 g, 4.0mmol). The mixture was stirred at room temperature overnight, thesolvent was evaporated under high vacuum and the residue was purified byflash column chromatography (0-5% ethyl acetate in methylene chloride)to give the title compound as a colorless oil (1.60 g, 89%). ¹ H-NMR(300 MHz, CDCl₃) δ9.10 (br s, 1H), 7.74 (br s, 1H), 7.35 (m, 5H), 5.55(br s, 1H), 5.10 (s, 2H), 4.12 (t, J=6.1 Hz, 2H), 3.32 (t, J=6.4 Hz,2H), 1.87 (pentet, J=6.2 Hz, 2H), 1.50 (s, 9H), 1.47 (s, 9H).

10. [N,N'-Di(tert-butoxycarbonyl)]3-amino-1-propoxyguanidine

A mixture of[N,N'-di(tert-butoxycarbonyl)]3-(benzyloxycarbonylamino)-1-propoxyguanidine(760 mg, 1.7 mmol), as prepared in the preceding step, and 10% Pd/C (80mg) in ethanol (20 mL) and tetrahydrofuran (20 mL) was hydrogenatedunder hydrogen (balloon) for 30 min. The catalyst was removed byfiltration through Celite, the filtrate was concentrated in vacuo, andthe residue was purified by Waters Sep-Pak (10 g, 95:5 methylenechloride:methanol saturated with ammonia) to give the title compound asa colorless oil (160 mg, 28%). ¹ H-NMR (300 MHz, CDCl₃) δ4.12 (t, J=6.1Hz, 2H), 2.85 (t, J=6.7 Hz, 2H), 1.84 (pentet, J=6.2 Hz, 2H), 1.50 (s,9H), 1.48 (s, 9H).

11.3-Benzylsulfonylamino-6-methyl-1-{([N,N'-di(tert-butoxycarbonyl)][3-(guanidinooxypropyl)aminocarbonylmethyl]}-2-pyridinone

To a solution of3-benzylsulfonylamino-6-methyl-1-carboxymethyl-2-pyridinone (152 mg,0.45 mmol), as prepared in the step 5,[N,N'-di(tert-butoxycarbonyl)]3-amino-1-propoxyguanidine (150 mg, 0.45mmol), as prepared in the preceding step, and diisopropylethylamine (90μL, 0.5 mmol) in N,N-dimethylformamide (10 mL) was added Castro'sreagent (BOP) (221 mg, 0.5 mmol). The mixture was stirred at roomtemperature overnight. Ethyl acetate (100 mL) was added, the solutionwashed with saturated NaHCO₃ (2×50 mL), 10% citric acid (2×50 mL) andbrine (50 mL), and dried over Na₂ SO₄. After evaporating the solvent invacuo, the residue was purified by Waters Sep-Pak (10 g, 4:1 ethylacetate:hexane) to give the title compound as a colorless foam (270 mg,92%). ¹ H-NMR (300 MHz, CDCl₃) δ9.02 (s, 1H), 8.70 (s, 1H), 8.58 (s,1H), 8.27 (t, J=5.6 Hz, 1H), 7.34 (m, 5H), 7.12 (d, J=7.6 Hz, 1H), 6.08(d, J=7.7 Hz, 1H), 4.70 (s, 2H), 4.50 (s, 2H), 3.88 (t, J=6.3 Hz, 2H),3.18 (t, J=6.4 Hz, 2H), 2.24 (s, 3H), 1.75 (t, J=6.5 Hz, 2H), 1.39 (s,18H).

12. 3-Benzylsulfonylamino-6-methyl-1-[(3-guanidinooxypropyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

A mixture of3-benzylsulfonylamino-6-methyl-1-{[N,N'-di(tert-butoxycarbonyl)][3-(guanidinooxypropyl)aminocarbonylmethyl]}-2-pyridinone(130 mg, 0.2 mmol), as prepared in the preceding step, andtrifluoroacetic acid (2 mL) in methylene chloride (5 mL) was stirred atroom temperature for 1 h. After evaporating the solvent in vacuo, theresidue was purified by Waters Sep-Pak (10 g, 10% methanol in methylenechloride) to give the title compound as a colorless foam (55 mg, 61%). ¹H-NMR (300 MHz, DMSO-d₆) δ8.57 (s, 1H), 8.35 (t, J=5.7 Hz, 1H), 7.62 (brs, 4H), 7.34 (m, 5H), 7.12 (d, J=7.5 Hz, 1H), 6.09 (d, J=7.7 Hz, 1H),4.70 (s, 2H), 4.52 (s, 2H), 3.81 (t, J=6.4 Hz, 2H), 3.20 (q, J=6.4 Hz,2H), 2.25 (s, 3H), 1.77 (pentet, J=6.5 Hz, 2H). Mass spectrum(MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₉ H₂₆ N₆O₅ S: 451.2 (M+H), 473.2 (M+Na); Found: 451.5, 473.5.

Example 23-Benzylsulfonylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR25## 1.N-[2-(Benzyloxycarbonylamino)ethoxy]phthalimide

To a solution of benzyl N-(2-hydroxyethyl)carbamate (5.9 g, 30 mmol),N-hydroxyphthalimide (4.9 g, 30 mmol), and triphenylphosphine (7.9 g, 30mmol) in tetrahydrofuran (100 mL) was added diethyl azodicarboxylate(5.2 g, 30 mmol). The reaction mixture was stirred at room temperatureovernight. Ethyl acetate (200 mL) was added, the solution washed withsaturated NaHCO₃ (2×100 mL) and brine (100 mL), and dried over Na₂ SO₄.After evaporating the solvent, the residue was purified by flash columnchromatography (methylene chloride to 4% ethyl acetate in methylenechloride) to give the title compound as a white solid (9.3 g, 91%). ¹H-NMR (300 MHz, CDCl₃) δ7.84 (m, 2H), 7.78 (m, 2H), 7.37 (m, 5H), 5.97(br s, 1H), 5.14 (s, 2H), 4.27 (t, J=4.9 Hz, 2H), 3.51 (q, J=5.2 Hz,2H).

2. 2-(Benzyloxycarbonylamino)ethoxyamine

To a solution of N-[2-(benzyloxycarbonylamino)ethoxy]phthalimide (1.36g, 4.0 mmol), as prepared in the preceding step, in ethanol (20 mL) andtetrahydrofuran (20 mL) was added 40% methylamine (2 mL, 25 mmol). Thereaction mixture was stirred at room temperature for 1 h. Afterevaporating the solvent, the residue was passed through silica gel (3:1ethyl acetate:hexane to ethyl acetate) to give the title compound as awhite solid (800 mg, 95%). ¹ H-NMR (300 MHz, CDCl₃) δ7.36 (m, 5H), 5.47(br s, 2H), 5.21 (br s, 1H), 5.10 (s, 2H), 3.72 (t, J=5.0 Hz, 2H), 3.44(q, J=5.0 Hz, 2H).

3. [N,N'-Di(tert-butoxycarbonyl)]2-(benzyloxycarbonylamino)ethoxyguanidine

To a solution of 2-(benzyloxycarbonylamino)ethoxyamine (780 mg, 3.7mmol), as prepared in the preceding step, in N,N-dimethylformamide (20mL) was added [N,N'-di(tert-butoxycarbonyl)]amidinopyrazole (1.25 g, 4.0mmol). The mixture was stirred at room temperature overnight, thesolvent was evaporated under high vacuum. The residue was purified byflash column chromatography (0-5% ethyl acetate in methylene chloride)to give the title compound as a colorless oil (1.55 g, 93%). ¹ H-NMR(300 MHz, CDCl₃) δ9.08 (s, 1H), 7.67 (s, 1H), 7.33 (m, 5H), 6.21 (br s,1H), 5.21 (br s, 1H), 5.11 (s, 2H), 4.12 (t, J=4.8 Hz, 2H), 3.54 (q,J=4.9 Hz, 2H), 1.49 (s, 9H), 1.46 (s, 9H).

4. [N,N'-Di(tert-butoxycarbonyl)]2-aminoethoxyguanidine

A mixture of[N,N'-di(tert-butoxycarbonyl)]2-(benzyloxycarbonylamino)ethoxyguanidine(730 mg, 1.5 mmol), as prepared in the preceding step, and 10% Pd/C (70mg) in ethanol (20 mL) and tetrahydrofuran (20 mL) was hydrogenatedunder hydrogen (balloon) for 30 min. The catalyst was removed byfiltration through Celite and the filtrate was concentrated in vacuo.The residue was purified by Waters Sep-Pak (10 g, 95:5 methylenechloride:methanol saturated with ammonia) to give the title compound asa colorless oil (290 mg, 61%). ¹ H-NMR (300 MHz, CDCl₃) δ9.08 (br s,1H), 4.08 (t, J=5.2 Hz, 2H), 2.99 (q, J=5.1 Hz, 2H), 1.50 (s, 9H), 1.48(s, 9H).

5.3-Benzylsulfonylamino-6-methyl-1-{([N,N'-di(tert-butoxycarbonyl)][2-(guanidinooxyethyl)aminocarbonylmethyl]}-2-pyridinone

To a solution of3-benzylsulfonylamino-6-methyl-1-carboxymethyl-2-pyridinone (152 mg,0.45 mmol), as prepared in the step 5 of Example 1,[N,N'-di(tert-butoxycarbonyl)]2-aminoethoxyguanidine (143 mg, 0.45mmol), as prepared in the preceding step, diisopropylethylamine (90 μL,0.5 mmol) in N,N-dimethylformamide (10 mL) was added Castro's reagent(BOP) (221 mg, 0.5 mmol). The mixture was stirred at room temperatureovernight. Ethyl acetate (100 mL) was added, the solution was washedwith saturated NaHCO₃ (2×50 mL), 10% citric acid (2×50 mL) and brine (50mL), and dried over Na₂ SO₄. After evaporating the solvent in vacuo, theresidue was purified by Waters Sep-Pak (10 g, 4:1 ethyl acetate:hexane)to give the title compound as a colorless foam (270 mg, 94%). ¹ H-NMR(300 MHz, CDCl₃) δ9.22 (s, 1H), 8.41 (t, J=5.0 Hz, 1H), 8.02 (s, 1H),7.62 (s, 1H), 7.34 (s, 1H), 7.29 (m, 5H), 5.99 (d, J=7.7 Hz, 1H), 4.89(s, 2H), 4.31 (s, 2H), 4.13 (t, J=5.0 Hz, 2H), 3.62 (q, J=5.1 Hz, 2H),2.30 (s, 3H), 1.52 (s, 9H), 1.48 (s, 9H).

6. 3-Benzylsulfonylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

A mixture of3-benzylsulfonylamino-6-methyl-1-{[N,N'-di(tert-butoxycarbonyl)][2-(guanidinooxyethyl)aminocarbonylmethyl]}-2-pyridinone(255 mg, 0.4 mmol), as prepared in the preceding step, andtrifluoroacetic acid (4 mL) in methylene chloride (8 mL) was stirred atroom temperature for 1 h. After evaporating the solvent in vacuo, theresidue was purified by Waters Sep-Pak (10 g, 10% methanol in methylenechloride) to give the title compound as a colorless foam (160 mg, 92%).¹ H-NMR (300 MHz, DMSO-d₆) δ8.58 (s, 1H), 8.49 (t, J=5.5 Hz, 1H), 7.73(br s, 4H), 7.35 (m, 5H), 7.13 (d, J=7.6 Hz, 1H), 6.11 (d, J=7.7 Hz,1H), 4.74 (s, 2H), 4.52 (s, 2H), 3.84 (t, J=5.3 Hz, 2H), 3.40 (m, 2H),2.26 (s, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acidmatrix) calcd. for C₁₈ H₂₄ N₆ O₅ S: 437.2 (M+H), 459.1 (M+Na); Found:437.3, 459.2.

Example 3 ##STR26##

a. A solution of the amine, 1 (0.025 g, 0.052 mmol) in dichIoromethane(2 mL) was treated with diethylaminoethyl polystyrene resin (Fluka,0.033 g, 0.098 mmol) and 4-iodobenzenesulfonyl chloride (0.03 g, 0.1mmol). The mixture was shaken at ambient temperature for five hoursbefore aminomethyl polystyrene resin (Adv. Chem. Tech., 0.1 g, 0.2 mmol)was added as a scavenger of excess sulfonyl chloride. Additionaldichloromethane (2 mL) was added and the mixture was shaken overnight.The reaction mixture, including the resins, was poured onto a silica gelcolumn (5 g SepPak) and eluted with a gradient of 10 to 50% ethylacetate in dichloromethane. The appropriate fractions were collected andevaporated to dryness on a Savant. Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₂₇ H₃₇ N₆ O₉SI-2t-Boc: 549.1. Found: 549.3. ##STR27##

b. A solution of the sulfonamide, 2 in dichloromethane (2 mL) wastreated with trifluoroacetic acid (1 mL) at ambient temperature andshaken for 4 h. The dichloromethane was removed on a Savant and theresidue was purified on a silica gel column (5 g SepPak) by elution with5% methanol in dichloromethane. The appropriate fractions were combinedand evaporated to dryness to give 19.6 mg (69% yield over 2 steps) of 3as a gum. ¹ H-NMR (300 Mhz, CDCl₃) δ10.95 (s, 1H), 9.48 (s, 1H), 8.42(t, 2H, J=5.6 Hz), 7.90 (d, 2H, J=8.6 Hz), 7.72 (s, 4H), 7.56 (d, 2H,J=8.6 Hz), 7.26 (d, 1H, J=7.5 Hz), 6.10 (d, 1H, J=7.7 Hz), 4.60 (s, 2H),3.96 (s, 2H), 3.80 (t, 2H, J=5.3 Hz), 2.20 (s, 3H). Mass spectrum (LCMS,ESI) calcd. for C₁₇ H₂₁ N₆ O₅ SI: 549.1. Found: 549.0.

c. [I-125]p-Iodobenzene sulfonyl chloride (A. S. Keston et al., J. Amer.Chem. Soc. 68:1390 (1946)) can be substituted in step a for thecold-iodo compound to form [I-125]3.

Example 43-Benzylsulfonylamino-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR28## 1.3-Benzylsulfonylamino-1-(tert-butoxycarbonylmethyl)-2-pyridinone

To a solution of 3-amino-1-(tert-butoxycarbonylmethyl)-2-pyridinone(1.12 g, 5.0 mmol), and N-methylmorpholine (1.5 mL, 10.0 mmol) inmethylene chloride (40 mL) was added α-toluenesulfonyl chloride (950 mg,5.0 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h.Additional methylene chloride (50 mL) was added. The resulting solutionwas washed with saturated NaHCO₃ (2×50 mL), 10% citric acid (3×50 mL)and brine (50 mL), and dried over Na₂ SO₄ and filtered and the filtratewas concentrated to give a solid which was washed with ethylacetate/hexane (1:2, 60 mL) to give the title compound as a white solid(1.8 g, 96%). ¹ H-NMR (300 MHz, CDCl₃) δ7.42 (br s, 1H), 7.36 (d, J=7.3Hz, 1H), 7.31 (m, 5H), 6.92 (d, J=7.0 Hz, 1H), 6.14 (t, J=7.2 Hz, 1H),4.58 (s, 2H), 4.34 (s, 2H), 1.51 (s, 9H).

2. 3-Benzylsulfonylamino-1-carboxymethyl-2-pyridinone

HCl gas was bubbled through a stirred suspension of3-benzylsulfonylamino-1-(tert-butoxycarbonylmethyl)-2-pyridinone (1.7 g,4.5 mmol), as prepared in the preceding step, in ethyl acetate (15 mL)at 0° C. until a solution was formed. After 2 h at room temperature, athick suspension was formed. The mixture was degassed with nitrogen andfiltered to give the title compound a white solid (1.4 g, 97%). ¹ H-NMR(300 MHz, CDCl₃) δ8.76 (s, 1H), 7.45 (dd, J=7.0, 1.8Hz, 1H), 7.32 (m,5H), 7.19 (dd, J=7.2, 1.8Hz, 1H), 6.16 (t, J=7.1 Hz, 1H), 4.69 (s, 2H),4.56 (s, 2H).

3.3-Benzylsulfonylamino-1-{([N,N'-di(tert-butoxycarbonyl)][2-(guanidinooxyethyl)aminocarbonylmethyl]}-2-pyridinone

To a solution of 3-benzylsulfonylamino-1-carboxymethyl-2-pyridinone (129mg, 0.4 mmol), as prepared in the preceding step,[N,N'-di(tert-butoxycarbonyl)]2-aminoethoxyguanidine (143 mg, 0.45mmol), as prepared in step 4 of Example 2, diisopropylethylamine (90 μL,0.5 mmol) in N,N-dimethylformamide (10 mL) was added Castro's reagent(BOP) (221 mg, 0.5 mmol). The mixture was stirred at room temperatureovernight. Ethyl acetate (100 mL) was added, the solution was washedwith saturated NaHCO₃ (2×50 mL), 10% citric acid (2×50 mL) and brine (50mL), and dried over Na₂ SO₄. After evaporating the solvent in vacuo, theresidue was purified by Waters Sep-Pak (10 g, 4:1 ethyl acetate:hexane)to give the title compound as a colorless foam (170 mg, 68%). ¹ H-NMR(300 MHz, CDCl₃) δ9.22 (s, 1H), 8.49 (br s, 1H), 7.44 (s, 1H), 7.34 (dd,J=7.3, 1.7 Hz, 1H), 7.29 (m, 5H), 7.02 (dd, J=7.0, 1.7 Hz, 1H), 6.12 (t,J=7.1 Hz, 1H), 4.73 (s, 2H), 4.34 (s, 2H), 4.15 (m, 2H), 3.65 (m, 2H),1.52 (s, 9H), 1.49 (s, 9H).

4.3-Benzylsulfonylamino-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

A mixture of3-benzylsulfonylamino-1-{[N,N'-di(tert-butoxycarbonyl)][2-(guanidinooxyethyl)aminocarbonylmethyl]}-2-pyridinone(155 mg, 0.25 mmol), as prepared in the preceding step, andtrifluoroacetic acid (2 mL) in methylene chloride (3 mL) was stirred atroom temperature for 2 h. After evaporation of the solvent in vacuo, theresidue was purified by Waters Sep-Pak (10 g, 10% methanol in methylenechloride) to give the title compound as a colorless foam (160 mg, 92%).¹ H-NMR (300 MHz, DMSO-d₆) δ11.00 (s, 1H), 8.66 (s, 1H), 8.45 (t, J=5.3Hz, 1H), 7.72 (br s, 4H), 7.40 (d, J=6.9 Hz, 1H), 7.33 (m, 5H), 7.19 (d,J=7.0 Hz, 1H), 6.19 (d, J=7.0 Hz, 1H), 4.62 (s, 2H), 4.55 (s, 2H), 3.83(t, J=5.1 Hz, 2H), 3.39 (m, 2H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₇ H₂₂ N₆ O₅ S: 423.1(M+H), 445.1 (M+Na); Found: 423.3, 445.0.

Example 53-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR29## 1.3-(3-Methylphenylsulfonyl)amino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone

To a solution of3-amino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone (1.42 g,5.88 mmol), as prepared in step 3 of Example 1, and N-methylmorpholine(1.29 mL, 11.76 mmol) in methylene chloride (40 mL) was added3-methylbenzenesulfonyl chloride (1.12 g, 5.88 mmol) at 0° C. Thereaction mixture was stirred at room temperature overnight. Additionalmethylene chloride (60 mL) was added. The resulting methylene chloridesolution was washed with saturated NaHCO₃ (2×50 mL), 10% citric acid(3×50 mL) and brine (50 mL), and dried over Na₂ SO₄. After evaporatingthe solvent, the residue was purified by flash column chromatography (5to 10% ethyl acetate in methylene chloride) to give the title compoundas a white solid (2.1 g, 91%). ¹ H-NMR (300 MHz, CDCl₃) δ7.63 (m, 2H),7.55 (br s, 1H), 7.42 (d, 1H, J=8 Hz), 7.32 (m, 2H), 6.01 (d, 1H, J=8Hz), 4.64 (s, 2H), 2.37 (s, 3H), 2.20 (s, 3H), 1.43 (s, 9H).

2. 3-(3-Methylphenylsulfonyl)amino-6-methyl-1-carboxymethyl-2-pyridinone

HCl gas was bubbled through a stirred suspension of3-(3-methylphenylsulfonyl)amino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone(2.0 g, 5.09 mmol), as prepared in the preceding step, in ethyl acetate(50 mL) at 0° C. until a solution was formed. After warming to roomtemperature over 2 h, a thick suspension was formed. The mixture wasdegassed with nitrogen and filtered to give the title compound as awhite solid (1.36 g, 80%). ¹ H-NMR (300 MHz, DMSO-d₆) δ9.38 (s, 1H),7.62 (m, 2H), 7.41 (m, 2H), 7.25 (d, 1H, J=8 Hz), 6.09 (d, 1H, J=8 Hz),4.67 (s, 2H), 2.35 (s, 3H), 2.20 (s, 3H).

3.3-(3-Methylphenylsulfonyl)amino-6-methyl-1-{[N,N'-di(tert-butoxycarbonyl)][2-(guanidinooxyethyl)aminocarbonylmethyl]}-2-pyridinone

To a solution of3-(3-methylphenylsulfonyl)amino-6-methyl-1-carboxymethyl-2-pyridinone(1.26 g, 3.75 mmol), as prepared in the preceding step,[N,N'-di(tert-butoxycarbonyl)]2-amino-1-ethoxyguanidine hydrochloride(1,33 g, 3.75 mmol) as prepared in step 4 of Example 2, anddiisopropylethylamine (1.29 g, 10.0 mmol) in N,N-dimethylformamide (30mL) was added Castro's reagent (BOP) (2.0 g, 4.47 mmol). The mixture wasstirred at room temperature overnight. Ethyl acetate (150 mL) was added,the solution was washed with saturated NaHCO₃ (2×50 mL), 10% citric acid(2×50 mL) and brine (50 mL), and dried over Na₂ SO₄. After evaporatingthe solvent in vacuo, the residue was purified twice by columnchromatography (1:1 ethyl acetate:hexane; then 2% methanol in methylenechloride) to give the title compound as a white solid (2.25 g, 92%). ¹H-NMR (300 MHz, CDCl₃) δ9.17 (s, 1H), 8.34 (t, J=5.1 Hz, 1H), 7.66 (m,4H), 7.48 (d, J=7.6 Hz, 1H), 7.32 (m, 2H), 6.00 (d, J=7.7 Hz, 1H), 4.80(s, 2H), 4.10 (t, J=5.3 Hz, 2H), 3.59 (q, J=5.4 Hz, 2H), 2.38 (s, 3H),2.25 (s, 3H), 1.55 (s, 9H), 1.45 (s, 9H).

4. 3-(3-Methylphenylsulfonyl)amino-6-methyl -1-[(3-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluorocaetate

A mixture of3-(3-methylphenylsulfonyl)amino-6-methyl-1-{[N,N'-di(tert-butoxycarbonyl)][3-(guanidinooxypropyl)aminocarbonylmethyl]}-2-pyridinone(2.24 g, 3.44 mmol), as prepared in the preceding step, andtrifluoroacetic acid (10 mL) in methylene chloride (20 mL) was stirredat room temperature for 4 h. After evaporating the solvent in vacuo, theresidue was purified by column chromatography (10% methanol in methylenechloride) to give the title compound as a white solid (1.59 g, 82%). ¹H-NMR (300 MHz, CD₃ OD) δ7.61 (m, 2H), 7.47 (d, 1H, J=7.6 Hz), 7.38 (m,2H), 6.20 (dd, 1H, J=7.7 Hz, 0.7 Hz), 4.70 (s, 2H), 3.93 (t, 2H, J=5.2Hz), 3.48 (t, 2H, J=5.2 Hz), 2.37 (s, 3H), 2.29 (s, 3H). Mass spectrum(LCMS, ESI) calcd. for C₁₈ H₂₄ SN₆ O₅ : 437.5 (M+H); found: 437.2.

5.3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(3-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonehydrochloride

3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(3-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluorocaetate (2.75 g, 5.0 mmol),as prepared in the preceding step, was treated with water (10 mL) andbrine (80 mL). The pH of the mixture was adjusted to 1 with 20%hydrochloride acid, the resulting mixture was stirred until the productcrystallized. The precipitate was collected by filtration, washed withice cold water, and oven dried in vacuo at 45° C. for two days to affordthe title compound as an off-white solid (2.25 g, 95%). mp: 177-179° C.¹ H-NMR (300 MHz, DMSO-d₆) δ11.1 (s, 1H), 9.3 (s, 1H), 8.6 (t, J=7.5 Hz,1H), 7.75 (br s, 4H), 7.42 (m, 4H), 7.25 (d, J=7.6 Hz, 1H), 6.10 (d,J=7.7 Hz,1H), 4.65 (s, 2H), 3.80 (t, J=5.2 Hz, 2H), 3.40 (q, J=5.2 Hz,2H), 2.35 (s, 3H), 2.24 (s, 3H). Mass spectrum (LCMS, ESI) calcd. forC₁₈ H₂₄ SN₆ O₅ : 437.5 (M+H); found: 437.2.

Example 63-(Benzyloxycarbonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR30##

The title compound was prepared form3-benzyloxycarbonylamino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone,as prepared in step 2 of Example 1, using the procedures in step 5 ofExample 1 and steps 5 & 6 of Example 2. ¹ H-NMR (300 MHz, DMSO-d₆)δ11.03 (s, 1H), 8.47 (t, J=5.4 Hz, 1H), 8.30 (s, 1H), 7.76 (br s, 4H),7.73 (d, J=7.5 Hz, 1H), 7.40 (m, 5H), 6.18 (d, J=7.7 Hz, 1H), 5.15 (s,2H), 4.73 (s, 2H), 3.82 (t, J=5.3 Hz, 2H), 3.38 (m, 2H), 2.24 (s, 3H).Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd.for C₁₉ H₂₄ N₆ O₅ : 417.2 (M+H), 439.2 (M+Na), 455.1 (M+K); Found:417.3, 439.4, 455.4.

Example 7 3-(Benzylsulfonyl)amino-6-methyl-1-[(1-(1-guanidinooxymethyl)cyclopropyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate##STR31## 1. 1-(Benzyloxycarbonylamino)cyclopropanemethanol

To a solution of 1-(benzyloxycarbonylamino)cyclopropanecarboxylic acid(500 mg, 2.1 mmol) in tetrahydrofuran (5 mL) at 0° C. was added B₂ H₆.THF (1M, 2.1 mL, 2.1 mmol). The mixture was stirred at ambienttemperature overnight, treated with K₂ CO₃ (1.0 g in 5 mL H₂ O) andextracted with methylene chloride (3×10 mL). The organic layer waswashed with brine (10 mL) and dried over Na₂ SO₄. After evaporating thesolvent, the residue was by chromatography (1:1 ethyl acetate:hexane) togive the title compound as a white solid (200 mg, 43%). ¹ H-NMR (300MHz, CDCl₃) δ7.35 (m, 5H), 5.30 (br s, 1H), 5.10 (s, 2H), 3.61 (s, 2H),3.02 (br s, 1H), 0.86 (s, 4H).

2. N-[1-(Benzyloxycarbonylamino)cyclopropanemethoxy]phthalimide

The title compound was prepared from 1-(benzyloxycarbonylamino)cyclopropanemethanol (200 mg, 0.9 mmol), as prepared in the precedingstep, using the procedure in step 1 of Example 2, as a white solid (295mg, 90%). ¹ H-NMR (300 MHz, CDCl₃) δ7.83 (m, 2H), 7.79 (m, 2H), 7.37 (m,5H), 6.23 (br s, 1H), 5.13 (s, 2H), 4.18 (s, 2H), 0.93 (m, 2H), 0.72 (m,2H).

3. [1-(Benzyloxycarbonylamino)cyclopropanemethoxy]amine

The title compound was prepared from N-[1-(benzyloxycarbonylamino)cyclopropanemethoxy]phthalimide (290 mg, 0.8 mmol), as prepared in thepreceding step, using the procedure in step 2 of Example 2, as acolorless oil (180 mg, 95%). ¹ H-NMR (300 MHz, CDCl₃) δ7.35 (m, 5H),5.60 (br s, 2H), 5.23 (br s, 1H), 5.09 (s, 2H), 3.64 (s, 2H), 0.89 (m,4H).

4. [N,N'-Di(tert-butoxycarbonyl)][1-(benzyloxycarbonylamino)cyclopropanemethoxy]guanidine

The title compound was prepared from [-(benzyloxycarbonylamino)cyclopropanemethoxy]amine (180 mg, 0.76 mmol), as prepared in thepreceding step, and (N,N'-di-tert-butoxycarbonyl)amidinopyrazole (280mg, 0.9 mmol) using the procedure in step 3 of Example 2, as a colorlessoil (330 mg, 91%). ¹ H-NMR (300 MHz, CDCl₃) δ9.10 (br s, 1H), 8.02 (brs, 1H), 7.35 (m, 5H), 5.74 (br s, 1H), 5.09 (s, 2H), 4.03 (s, 2H), 1.49(s, 9H), 1.47 (s, 9H), 0.91 (m, 4H).

5. [N,N'-Di(tert-butoxycarbonyl)](1-aminocyclopropanemethoxy) guanidine

The title compound was prepared from[N,N'-di(tert-butoxycarbonyl)][1-(benzyloxycarbonylamino)cyclopropanemethoxy]guanidine(330 mg, 0.69 mmol), as prepared in the preceding step, using theprocedure in step 4 of Example 2, as a colorless oil (200 mg, 84%). ¹H-NMR (300 MHz, CDCl₃) δ9.09 (br s, 1H), 3.96 (s, 2H), 1.52 (s, 9H),1.48 (s, 9H), 0.67 (m, 2H), 0.60 (m, 2H).

6.3-Benzylsulfonylamino-6-methyl-1-{[N,N'-di(tert-butoxycarbonyl)][1-(1-(guanidinooxymethyl)cyclopropylamino)carbonylmethyl]}-2-pyridinone

The title compound was prepared from[N,N'-di(tert-butoxycarbonyl)](1-aminocyclopropanemethoxy)guanidine (100mg, 0.3 mmol), as prepared in the preceding step, and3-benzylsulfonylamino-6-methyl-1-carboxymethyl-2-pyridinone (100 mg, 0.3mmol), as prepared in the step 5 of Example 1, using the procedure instep 5 of Example 2, as a colorless foam (120 mg, 60%). ¹ H-NMR (300MHz, CDCl₃) δ9.08 (br s, 1H), 7.74 (s, 1H), 7.72 (s, 1H), 7.31 (d, J=7.5Hz, 1H), 7.26 (m, 5H), 6.00 (d, J=7.7 Hz, 1H), 4.79 (s, 2H), 4.30 (s,2H), 3.97 (s, 2H), 2.31 (s, 3H), 1.51 (s, 9H), 1.48 (s, 9H), 1.04 (m,2H), 0.87 (m, 2H).

7. 3-(Benzylsulfonyl)amino-6-methyl-1-[(1-(1-guanidinooxymethyl)cyclopropyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

The title compound was prepared form3-benzylsulfonylamino-6-methyl-1-{[N,N'-di(tert-butoxycarbonyl)][1-(1-(guanidinooxymethyl)cycloamino)carbonylmethyl]}-2-pyridinone(110 mg, 0.166 mmol), as prepared in the preceding step, using theprocedure in step 6 of Example 2, as a white solid (85 mg, 89%). ¹ H-NMR(300 MHz, DMSO-d₆) δ1.88 (br s, 1H), 8.78 (s, 1H), 8.60 (s, 1H), 7.73(br s, 4H), 7.33 (m, 5H), 7.13 (d, J=7.5 Hz, 1H), 6.11 (d, J=7.7 Hz,1H), 4.71 (s, 2H), 4.50 (s, 2H), 3.80 (s, 2H), 2.23 (s, 3H), 0.86 (m,2H), 0.78 (m, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamicacid matrix) calcd. for C₂₀ H₂₆ N₆ O₅ S: 463.2 (M+H), 485.2 (M+Na);Found: 463.1, 485.2.

Example 8 3-(Benzylsulfonyl)amino-6-methyl-1-[(4-guanidinooxy)piperidinylcarbonylmethyl]-2-pyridinone trifluoroacetate ##STR32##

The title compound was prepared from 4-hydroxypiperidine using theprocedures in steps 6-10 of Example 1 and steps 5 & 6 of Example 2, as acolorless foam. ¹ H-NMR (300 MHz, DMSO-d₆) δ11.14 (s, 1H), 8.57 (s, 1H),7.74 (br s, 4H), 7.34 (m, 5H), 7.12 (d, J=7.6 Hz, 1H), 6.09 (d, J=7.9Hz, 1H), 5.02 (s, 2H), 4.52 (s, 2H), 3.89 (m, 3H), 3.36 (m, 1H), 3.13(m, 1H), 2.20 (s, 3H), 2.00 (m, 1H), 1.81 (m, 1H), 1.72 (m, 1H), 1.56(m, 1H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acidmatrix) calcd. for C₂₁ H₂₈ N₆ O₅ S: 477.2 (M+H), 499.2 (M+Na), 515.1(M+K); Found: 477.0, 498.9, 514.9.

Example 93-(3-Chlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate ##STR33## 1.3-Chlorobenzylsulfonyl chloride

A mixture of 3-chlorobenzyl chloride (1.61 g, 10 mmol) and sodiumthiosulfate (1.6 g, 10 mmol) in methanol (10 mL) and water (10 mL) washeated to reflux for 3 h. The mixture was cooled to 0° C. and glacialacetic acid (10 mL) and ice were added. Chlorine gas was bubbled throughthe resulting suspension for 40 min, periodically adding ice to maintainan ice/liquid mixture. After an additional 1 h, the mixture wasextracted with ether (3×20 mL), the combined extracts were washed with5% sodium bisulfite (2×20 mL), brine (20 mL) and dried over Na₂ SO₄.After evaporating the solvent, the residue was purified by flash columnchromatography (methylene chloride) to give the title compound as awhite solid (1.5 g, 67%). ¹ H-NMR (300 MHz, CDCl₃) δ7.30-7.50 (m, 4H),4.83 (s, 2H).

2.3-(3-Chlorobenzylsulfonyl)amino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone

The title compound was prepared from 3-chlorobenzylsulfonyl chloride(113 mg, 0.5 mmol), as prepared in the preceding step, and3-amino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone (120 mg, 0.5mmol), as prepared in step 3 of Example 1, using the procedure in step 4of Example 1, as a white solid (180 mg, 84%). ¹ H-NMR (300 MHz, CDCl₃)δ7.37 (d, J=7.6 Hz, 1H), 7.30 (m, 4H), 7.20 (s, 1H), 6.02 (d, J=7.7 Hz,1H), 4.78 (s, 2H), 4.27 (s, 2H), 2.27 (s, 3H), 1.50 (s, 9H).

3. 3-(3-Chlorobenzylsulfonyl)amino-6-methyl-1-carboxymethyl-2-pyridinone

The title compound was prepared from3-(3-chlorobenzylsulfonyl)amino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone(170 mg, 0.4 mmol), as prepared in the preceding step, using theprocedure in step 5 of Example 1, as an off white solid (150 mg, 100%).¹ H-NMR (300MHz, CDCl₃) δ8.83 (s, 1H), 7.45 (s, 1H), 7.37 (m, 3H), 7.18(d, J=7.5 Hz, 1H), 6.11 (d, J=7.6 Hz, 1H), 4.79 (s, 2H), 4.56 (s, 2H),2.27 (s, 3H).

4.3-(3-Chlorobenzylsulfonyl)amino-6-methyl-1-{[N,N'-di(tert-butoxycarbonyl)][2-(guanidinooxyethyl)aminocarbonylmethyl]}-2-pyridinone

The title compound was prepared from3-(chlorobenzylsulfonyl)amino-6-methyl-1-carboxymethyl-2-pyridinone (140mg, 0.38 mmol), as prepared in the preceding step, and[N,N'-di(tert-butoxycarbonyl)]2-aminoethoxyguanidine (120 mg, 0.38mmol), as prepared in step 4 of Example 2, using the procedure in step 5of Example 2, as a colorless foam (140 mg, 57%). ¹ H-NMR (300 MHz,CDCl₃) δ9.20 (s, 1H), 8.46 (br s, 1H), 8.02 (s, 1H), 7.59 (s, 1H), 7.32(m, 3H), 7.18 (m, 1H), 6.00 (d, J=7.7 Hz, 1H), 4.91 (s, 2H), 4.26 (s,2H), 4.14 (t, J=5.3Hz, 2H), 3.63 (q, J=5.2Hz, 2H), 2.31 (s, 3H), 1.52(s, 9H), 1.49 (s, 9H).

5. 3-(3-Chlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate

The title compound was prepared from3-(3-chlorobenzylsulfonyl)amino-6-methyl-1-{[N,N'-di(tert-butoxycarbonyl)][2-(guanidinooxyethyl)aminocarbonylmethyl]}-2-pyridinone(140 mg, 0.22 mmol), as prepared in the preceding step, using theprocedure in step 6 of Example 2, as a white solid (95 mg, 74%). ¹ H-NMR(300 MHz, DMSO-d₆) δ11.00 (s, 1H), 8.74 (s, 1H), 8.49 (t, J=5.5 Hz, 1H),7.74 (br s, 4H), 7.45 (s, 1H), 7.40 (m, 3H), 7.18 (d, J=7.5 Hz, 1H),6.12 (d, J=7.7 Hz, 1H), 4.75 (s, 2H), 4.56 (s, 2H), 3.83 (t, J=5.4 Hz,2H), 3.41 (m, 2H), 2.26 (s, 3H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₈ H₂₃ ClN₆ O₅ S:471.1 (M+H), 493.1 (M+Na), 509.1 (M+K); Found: 471.2, 493.2, 509.2.

The following compounds (Example 10 to Example 27) were prepared in amanner analogous to Example 9.

Example 103-(3-Trifluoromethylbenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR34## ¹ H-NMR (300 MHz, DMSO-d₆) δ10.97 (s, 1H),8.79 (s, 1H), 8.50 (t, J=4.6 Hz, 1H), 7.74 (br s, 4H), 7.68 (m, 4H),7.17 (d, J=7.5 Hz, 1H), 6.11 (d, J=7.5 Hz, 1H), 4.74 (s, 2H), 4.68 (s,2H), 3.83 (t, J=5.4 Hz, 2H), 3.41 (m, 2H), 2.25 (s, 3H). Mass spectrum(MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₉ H₂₃ F₃N₆ O₅ S: 505.1 (M+H), 527.1 (M+Na), 543.1 (M+K); Found: 505.1, 527.1,543.1. Example 113-(2-Trifluoromethylbenzyl)sulfonylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR35## ¹ H-NMR (300 MHz, DMSO-d₆) δ11.00 (s, 1H),9.12 (s, 1H), 8.50 (t, J=5.5 Hz, 1H), 7.75 (br s, 4H), 7.68 (m, 3H),7.57 (m, 1H), 7.24 (d, J=7.6 Hz, 1H), 6.16 (d, J=7.7 Hz, 1H), 4.76 (s,2H), 4.66 (s, 2H), 3.83 (t, J=5.4 Hz, 2H), 3.39 (m, 2H), 2.28 (s, 3H).Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd.for C₁₉ H₂₃ F₃ N₆ O₅ S: 505.1 (M+H), 527.1 (M+Na); Found: 505.1, 527.1Example 123-(2-Iodobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate ##STR36## ¹ H-NMR(300 MHz, DMSO-d₆) δ11.06 (s, 1H), 8.90 (s, 1H), 8.51 (t, J=5.5 Hz, 1H),7.89 (d, J=7.9 Hz, 1H), 7.78 (br s, 4H), 7.52 (d, J=7.7 Hz, 1H), 7.39(t, J=7.5 Hz, 1H), 7.24 (d, J=7.5 Hz, 1H), 7.09 (t, J=7.6 Hz, 1H), 6.15(d, J=7.7 Hz, 1H), 4.75 (s, 2H), 4.65 (s, 2H), 3.83 (t, J=5.4 Hz, 2H),3.41 (m, 2H), 2.27 (s, 3H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₈ H₂₃ IN₆ O₅ S:563.1 (M+H), 585.1 (M+Na); Found: 562.7, 584.7. Example 133-(2-Chlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate ##STR37## ¹ H-NMR(300 MHz, DMSO-d₆) δ10.95 (s, 1H), 8.90 (s, 1H), 8.50 (t, J=5.5 Hz, 1H),7.70 (br s, 4H), 7.54 (d, J=7.1 Hz, 1H), 7.48 (d, J=7.5 Hz, 1H), 7.36(t, J=7.3 Hz, 2H), 7.20 (d, J=7.5 Hz, 1H), 6.14 (d, J=7.7 Hz, 1H), 4.75(s, 2H), 4.66 (s, 2H), 3.83 (t, J=5.3 Hz, 2H), 3.41 (m, 2H), 2.27 (s,3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix)calcd. for C₁₈ H₂₃ ClN₆ O₅ S: 471.1 (M+H), 493.1 (M+Na); Found: 470.7,492.7. Example 143-(2-Bromobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate ##STR38## ¹ H-NMR(300 MHz, DMSO-d₆) δ10.99 (s, 1H), 8.91 (s, 1H), 8.50 (t, J=5.6 Hz, 1H),7.74 (br s, 4H), 7.65 (d, J=7.8 Hz, 1H), 7.55 (d, J=7.6 Hz, 1H), 7.38(t, J=7.5 Hz, 1H), 7.29 (t, J=7.7 Hz, 1H), 7.21 (d, J=7.5 Hz, 1H), 6.14(d, J=7.7 Hz, 1H), 4.75 (s, 2H), 4.67 (s, 2H), 3.83 (t, J=5.3 Hz, 2H),3.41 (m, 2H), 2.27 (s, 3H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₈ H₂₃ BrN₆ O₅ S:515.1 (M+H), 537.1 (M+Na); Found: 514.8, 536.7. Example 153-(3-Fluorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate ##STR39## ¹ H-NMR(300 MHz, DMSO-d₆) δ10.92 (s, 1H), 8.73 (s, 1H), 8.49 (t, J=5.4 Hz, 1H),7.69 (br s, 4H), 7.38 (m, 1H), 7.22 (m, 3H), 7.17 (d, J=7.5 Hz, 1H),6.12 (d, J=7.7 Hz, 1H), 4.74 (s, 2H), 4.56 (s, 2H), 3.83 (t, J=5.3 Hz,2H), 3.39 (m, 2H), 2.26 (s, 3H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₈ H₂₃ FN₆ O₅ S:455.2 (M+H), 477.1 (M+Na), 493.1 (M+K); Found: 455.3, 477.3, 493.2.Example 163-(4-Chlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate ##STR40## ¹ H-NMR(300 MHz, DMSO-d₆) δ11.02 (s, 1H), 8.66 (s, 1H), 8.50 (t, J=5.5 Hz, 1H),7.75 (br s, 4H), 7.39 (s, 4H), 7.16 (d, J=7.5 Hz, 1H), 6.11 (d, J=7.6Hz, 1H), 4.74 (s, 2H), 4.54 (s, 2H), 3.83 (t, J=5.4 Hz, 2H), 3.41 (m,2H), 2.26 (s, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamicacid matrix) calcd. for C₁₈ H₂₃ ClN₆ O₅ S: 471.1 (M+H), 493.1 (M+Na);Found: 471.1, 493.1. Example 173-((2-Chloro-6-fluoro)benzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR41## ¹ H-NMR (300 MHz, DMSO-d₆) δ10.96 (s, 1H),9.11 (s, 1H), 8.49 (t, J=5.5 Hz, 1H), 7.71 (br s, 4H), 7.45 (dd, J=8.1,2.1 Hz, 1H), 7.37 (d, J=7.6 Hz, 1H), 7.28 (d, J=8.1 Hz, 1H), 7.23 (d,J=7.5 Hz, 1H), 6.16 (d, J=7.8 Hz, 1H), 4.74 (s, 2H), 4.68 (s, 2H), 3.83(t, J=5.4 Hz, 2H), 3.40 (t, J=5.3 Hz, 2H), 2.27 (s, 3H). Mass spectrum(MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₈ H₂₂ClFN₆ O₅ S: 489.1 (M+H), 511.1 (M+Na); Found: 488.9, 510.9. Example 183-(2-Fluorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate ##STR42## ¹ H-NMR(300 MHz, DMSO-d₆) δ11.03 (s, 1H), 8.86 (s, 1H), 8.51 (t, J=5.5 Hz, 1H),7.76 (br s, 4H), 7.47 (m, 2H), 7.20 (m, 3H), 6.13 (d, J=7.7 Hz, 1H),4.74 (s, 2H), 4.55 (s, 2H), 3.83 (t, J=5.5 Hz, 2H), 3.39 (t, J=5.6 Hz,2H), 2.26 (s, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamicacid matrix) calcd. for C₁₈ H₂₃ FN₆ O₅ S: 455.2 (M+H), 477.1 (M+Na);Found: 455.0, 477.1. Example 193-(4-Fluorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone trifluoroacetate ##STR43## ¹ H-NMR(300 MHz, DMSO-d₆) δ11.04 (s, 1H), 8.63 (s, 1H), 8.51 (t, J=5.6 Hz, 1H),7.76 (br s, 4H), 7.39 (m, 2H), 7.16 (m, 3H), 6.11 (d, J=7.7 Hz, 1H),4.74 (s, 2H), 4.53 (s, 2H), 3.84 (t, J=5.3 Hz, 2H), 3.41 (t, J=5.5 Hz,2H), 2.25 (s, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamicacid matrix) calcd. for C₁₈ H₂₃ FN₆ O₅ S: 455.2 (M+H), 477.1 (M+Na);Found: 455.0, 476.9. Example 203-(2,3-Dichlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR44## ¹ H-NMR (300 MHz, DMSO-d₆) δ10.92 (s, 1H),9.02 (s, 1H), 8.49 (t, J=5.5 Hz, 1H), 7.69 (br s, 4H), 7.64 (d, J=8.0Hz, 1H), 7.54 (d, J=7.7 Hz, 1H), 7.36 (t, J=7.9 Hz, 1H), 7.23 (d, J=7.5Hz, 1H), 6.15 (d, J=7.7 Hz, 1H), 4.75 (s, 4H), 3.83 (t, J=5.3 Hz, 2H),3.41 (t, J=5.5 Hz, 2H), 2.27 (s, 3H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₈ H₂₂ Cl₂ N₆ O₅ S:505.1 (M+H), 527.1 (M+Na); Found: 504.8, 527.1. Example 213-(3,4-Difluorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR45## ¹ H-NMR (300 MHz, DMSO-d₆) δ10.99 (s, 1H),8.77 (s, 1H), 8.49 (t, J=5.5 Hz, 1H), 7.67 (br s, 4H), 7.49 (m, 1H),7.42 (m, 1H), 7.24 (m, 1H), 7.19 (d, J=7.5 Hz, 1H), 6.13 (d, J=7.7 Hz,1H), 4.74 (s, 2H), 4.54 (s, 2H), 3.83 (t, J=5.3 Hz, 2H), 3.39 (t, J=5.4Hz, 2H), 2.26 (s, 3H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₈ H₂₂ F₂ N₆ O₅ S:473.1 (M+H), 495.1 (M+Na); Found: 473.1, 495.1. EXAMPLE 223-(2,4-Dichlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR46##

¹ H-NMR (300 MHz, DMSO-d₆) δ 10.99 (s, 1H), 8.99 (s, 1H), 8.51 (t, J=5.5Hz, 1H), 7.74 (br s, 4H), 7.66 (s, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.44 (d,J=8.3 Hz, 1H), 7.22 (d, J=7.6 Hz, 1H), 6.15 (d, J=7.9 Hz, 1H), 4.75 (s,2H), 4.66 (s, 2H), 3.83 (t, J=5.3 Hz, 2H), 3.41 (t, J=5.2 Hz, 2H), 2.27(s, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acidmatrix) calcd. for C₁₈ H₂₂ Cl₂ N₆ O₅ S: 505.1 (M+H), 527.1 (M+Na);Found: 505.1, 527.1.

EXAMPLE 233-(2,5-Dichlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR47##

¹ H-NMR (300 MHz, DMSO-d₆) δ 10.95 (s, 1H), 9.07 (s, 1H), 8.49 (t, J=5.5Hz, 1H), 7.71 (br s, 4H), 7.66 (s, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.45 (d,J=8.6 Hz, 1H), 7.24 (d, J=7.5 Hz, 1H), 6.15 (d, J=7.8 Hz, 1H), 4.76 (s,2H), 4.67 (s, 2H), 3.83 (t, J=5.4 Hz, 2H), 3.38 (t, J=5.5 Hz, 2H), 2.27(s, 3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acidmatrix) calcd. for C₁₈ H₂₂ Cl₂ N₆ O₅ S: 505.1 (M+H), 527.1 (M+Na);Found: 505.1, 526.9.

EXAMPLE 243-(3,4-Dichlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR48##

¹ H-NMR (300 MHz, DMSO-d₆) δ 10.96 (s, 1H), 8.82 (s, 1H), 8.50 (t, J=5.5Hz, 1H), 7.72 (br s, 4H), 7.66 (s, 1H), 7.61 (d, J=8.3 Hz, 1H), 7.60 (d,J=8.3 Hz, 1H), 7.22 (d, J=7.6 Hz, 1H), 6.12 (d, J=7.7 Hz, 1H), 4.75 (s,2H), 4.59 (s, 2H), 3.83 (t, J=5.4 Hz, 2H), 3.38 (m, 2H), 2.26 (s, 3H).Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd.for C₁₈ H₂₂ Cl₂ N₆ O₅ S: 505.1 (M+H), 527.1 (M+Na); Found: 504.8, 526.8.

EXAMPLE 253-(1-naphthalenylmethylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR49##

¹ H-NMR (300 MHz, DMSO-d₆) δ 11.02 (s, 1H), 8.72 (s, 1H), 8.51 (t, J=5.5Hz, 1H), 8.20 (m, 1H), 7.93 (m, 1H), 7.75 (br s, 4H), 7.67 (m, 1H), 7.53(m, 4H), 7.16 (d, J=7.5 Hz, 1H), 6.10 (d, J=7.5 Hz, 1H), 5.08 (s, 2H),4.74 (s, 2H), 3.84 (t, J=5.2 Hz, 2H), 3.42 (t, J=5.3 Hz, 2H), 2.26 (s,3H). Mass spectrum (LCMS, ESI) calcd. for C₂₂ H₂₆ N₆ O₅ S: 487.5 (M+H);Found: 487.8.

EXAMPLE 263-(2-naphthalenylmethylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR50##

¹ H-NMR (300 MHz, DMSO-d₆) δ 11.06 (s, 1H), 8.62 (s, 1H), 8.52 (t, J=5.3Hz, 1H), 7.86 (m, 4H), 7.78 (br s, 4H), 7.52 (m, 3H), 7.21 (d, J=7.5 Hz,1H), 6.07 (d, J=7.7 Hz, 1H), 4.74 (s, 2H), 4.69 (s, 2H), 3.85 (t, J=5.2Hz, 2H), 3.43 (t, J=5.3 Hz, 2H), 2.22 (s, 3H). Mass spectrum (LCMS, ESI)calcd. for C₂₂ H₂₆ N₆ O₅ S: 487.5 (M+H); Found: 487.1.

EXAMPLE 273-(2-Methylbenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR51##

¹ H-NMR (300 MHz, DMSO-d₆) δ 11.07 (s, 1H), 8.72 (s, 1H), 8.51 (t, J=5.5Hz, 1H), 7.78 (br s, 4H), 7.21 (m, 4H), 7.12 (d, J=7.5 Hz, 1H), 6.11 (d,J=7.7 Hz, 1H), 4.75 (s, 2H), 4.54 (s, 2H), 3.83 (t, J=5.4 Hz, 2H), 3.41(t, J=5.4 Hz, 2H), 2.34 (s, 3H), 2.26 (s, 3H). Mass spectrum (LCMS, ESI)calcd. for C₁₉ H₂₆ N₆ O₅ S: 451.3 (M+H); Found: 451.2.

EXAMPLE 283-(3-Chlorobenzylsulfonyl)-N-methylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR52## 1.3-(3-Chlorobenzylsulfonyl)-N-methylamino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone

To a suspension of3-(3-chlorobenzylsulfonyl)amino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone(190 mg, 0.44 mmol), as prepared in step 2 of Example 9, and potassiumcarbonate (276 mg, 2.0 mmol) in acetonitrile (10 mL) was addediodomethane (142 mg, 1.0 mmol). The mixture was stirred at ambienttemperature overnight. Water (50 mL) was added to the mixture, extractedwith ethyl acetate (3×30 mL). The organic layer was washed with brine(2×30 mL) and dried over Na₂ SO₄. The solvent was evaporated to give thetitle compound as a colorless foam (195 mg, 100%). ¹ H-NMR (300 MHz,CDCl₃) δ 7.51 (s, 1H), 7.48 (d, J=7.5 Hz, 1H), 7.33 (m, 3H), 6.11 (d,J=7.6 Hz, 1H), 4.75 (s, 2H), 4.38 (s, 2H), 3.22 (s, 3H), 2.33 (s, 3H),1.49 (s, 9H).

2.3-(3-Chlorobenzylsulfonyl)-N-methylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

The title compound was prepared from3-(3-chlorobenzylsulfonyl)-N-methylamino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone,as prepared in the preceding step, using the procedures in step 5 ofExample 1 and steps 5 and 6 of Example 2, as a white solid. ¹ H-NMR (300MHz, DMSO-d₆) δ 10.97 (s, 1H), 8.50 (t, J=5.5 Hz, 1H), 7.73 (br s, 4H),7.53 (s, 1H), 7.42 (m, 3H), 7.37 (d, J=7.5 Hz, 1H), 6.12 (d, J=7.5 Hz,1H), 4.76 (s, 2H), 4.53 (s, 2H), 3.83 (t, J=5.4 Hz, 2H), 3.39 (t, J=5.5Hz, 2H), 3.05 (s, 3H), 2.31 (s, 3H). Mass spectrum (MALDI-TOF,α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₉ H₂₅ ClN₆ O₅ S:485.1 (M+H), 507.1 (M+Na); Found: 485.1, 507.1.

EXAMPLE 293-(3,4-Dichlorobenzylsulfonyl)-N-methylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR53##

The title compound was prepared in a manner analogous to Example 28. ¹H-NMR (300 MHz, DMSO-d₆) δ 10.97 (s, 1H), 8.51 (t, J=5.5 Hz, 1H), 7.74(br s, 5H), 7.66 (d, J=8.2 Hz, 1H), 7.45 (m, 1H), 7.42 (d, J=7.5 Hz,1H), 6.22 (d, J=7.6 Hz, 1H), 4.77 (s, 2H), 4.55 (s, 2H), 3.83 (t, J=5.3Hz, 2H), 3.39 (t, J=5.6 Hz, 2H), 3.05 (s, 3H), 2.32 (s, 3H). Massspectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₁₉ H₂₄ Cl₂ N₆ O₅ S 519.1 (M+H), 541.1 (M+Na); Found: 519.3, 541.4.

EXAMPLE 303-(2-Chlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR54## 1.3-(Benzyloxycarbonyl)amino-6-methyl-1-carboxymethyl-2-pyridinone:

To a solution of3-benzyloxycarbonylamino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone(6.0 g, 17 mmol), as prepared in step 2 of Example 1, in methylenechloride (12 mL) was added trifluoroacetic acid (12 mL) and the reactionstirred at ambient temperature. After 30 minutes the reaction wasconcentrated in vacuo, dissolved in methylene chloride, and diluted withhexane. The precipitated product was collected by filtration and driedin vacuo giving a quantitative yield of white solid. ¹ H NMR (300 MHz,DMSO-d₆) δ 13.17 (br s, 1 H), 8.36 (s, 1H), 7.74 (d, 1H, J=7.5 Hz), 7.35(m, 5H), 6.18 (d, 1H, J=7.7 Hz), 5.15 (s, 2H), 4.77 (s, 2H), 2.25 (s,3H).

2. 3-Benzyloxycarbonylamino-6-methyl-1-{[N,N'-di(tert-butoxycarbonyl)][2-(guanidinooxyethyl)aminocarbonyl]}-2-pyridinone:

To a solution of3-(benzyloxycarbonyl)amino-6-methyl-1-carboxymethyl-2-pyridinone (0.85g, 2.5 mmol), as prepared in the preceding step, and[N,N'-di(tert-butoxycarbonyl)] 3-amino-1-ethoxyguanidine (0.86 g, 2.7mmol), as prepared in step 4 of Example 2, in N,N-dimethylformamide (42mL), was added N,N-diisopropylethylamine (0.59 mL, 3.4 mmol) andCastro's reagent (BOP; 1.31 g, 3.0 mmol). After stirring 2 hours atambient temperature, the reaction was concentrated in vacuo and thecrude product recrystallized from 3:1 ethyl acetate:hexane giving acolorless solid. ¹ H NMR (300 MHz, DMSO-d₆) δ 9.11 (s, 1H), 8.71 (s,1H), 8.36 (m, 1H), 8.30 (s, 1H), 7.74 (d, 1H, J=7.6 Hz), 7.37 (m, 5H),6.16 (d, 1H, J=8.1 Hz), 5.15 (s, 2H), 4.72 (s, 2H), 3.87 (t, 2H, J=5Hz), 3.39 (m, 2H), 2.81 (d, 2H, J=11 Hz), 2.24 (s, 3H), 1.42 (s, 9H),1.39 (s, 9H).

3. 3-Amino-6-methyl-1-{[N,N'-di(tert-butoxycarbonyl)][2-(guanidinooxyethyl)aminocarbonyl]}-2-pyridinone:

To a solution of3-benzyloxycarbonylamino-6-methyl-1-{[N,N'-di(tert-butoxycarbonyl)][2-(guanidinooxyethyl)aminocarbonyl]}-2-pyridinone (0.80 g, 1.3 mmol),as prepared in the preceding step, in 2:1 ethanol:tetrahydrofuran (96mL) was added 10% palladium (0) on activated carbon (64 mg). Afterdegassing and backfilling with nitrogen, the reaction was stirred underhydrogen gas at atmospheric pressure for 1 hour, filtered throughCelite, and the filtrate concentrated in vacuo giving a colorless solidthat was used without further purification.

4.3-(2-Chlorophenylsulfonyl)amino-6-methyl-1-{[N,N'-di(tert-butoxycarbonyl)][2-(guanidinooxyethyl)aminocarbonyl]}-2-pyridinone:

To a solution of 3-amino-6-methyl-1-{[N,N'-di(tert-butoxycarbonyl)][2-(guanidinooxyethyl)aminocarbonyl]}-2-pyridinone (0.11 g, 0.23 mmol),as prepared in the preceding step, in methylene chloride (4 mL) wasadded 2-chlorobenzenesulfonyl chloride (0.048 g, 0.23 mmol) andN-methylmorpholine (0.024 mL, 0.22 mmol). After stirring 4 hours atambient temperature, the reaction was diluted with additional methylenechloride and washed with saturated aqueous NaHCO₃, 10% aqueous citricacid, and brine. The organic layer was then separated and evaporated invacuo and the crude product used without further purification.

5.3-(2-Chlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate:

3-(2-Chlorophenylsulfonyl)amino-6-methyl-1-{[N,N'-di(tert-butoxycarbonyl)][2-(guanidinooxyethyl)aminocarbonyl]}-2-pyridinone, as prepared in thepreceding step, was dissolved in methylene chloride (ca. 4 mL) andtreated with neat trifluoroacetic acid (ca. 2 mL) at ambient temperaturefor 4 hours. After evaporation, the crude product was dissolved inmethylene chloride, washed with saturated aqueous NaHCO₃, 10% aqueouscitric acid, and brine, dried over Na₂ SO₄, filtered and evaporated. Thecrude product was then purified on a Waters silica Sep-Pak (gradientelution: 10-50% ethyl acetate in methylene chloride) giving the titlecompound (0.11 g, 89%). ¹ H NMR (300 MHz, DMSO-d₆) δ 10.97 (s, 1H), 9.21(s, 1H), 8.45 (t, 1H. J=5.6 Hz), 8.01 (m, 1H), 7.73 (br s, 4H), 7.64 (m,2H), 7.49 (m, 1H), 7.21 (d, 1H, J=7.6 Hz), 6.08 (d, 1H, J=7.9 Hz), 4.64(s, 2H), 3.80 (t, 2H, J=5.3 Hz), 3.40 (m, 2H), 2.19 (s, 3H). Massspectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₁₇ H₂₁ N₆ O₅ SCl: 479.1 (M+Na), 457.1 (M+H). Found: 479.4, 457.3.

EXAMPLE 313-(4-Chlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR55##

The title compound was prepared as in Example 30 starting with4-chlorobenzenesulfonyl chloride (0.048 g, 0.23 mmol). ¹ H NMR (300 MHz,DMSO-d₆) δ 10.94 (s, 1H), 9.50 (s, 1H), 8.41 (t, 1H, J=5.6 Hz), 7.80 (m,2H), 7.69 (br s, 4H), 7.60 (m, 2H), 7.28 (d, 1H, J=7.6 Hz), 6.11 (d, 1H,J=7.7 Hz), 4.60 (s, 2H), 3.79 (t, 2H, J=5.3 Hz), 3.39 (m, 2H), 2.20 (s,3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix)calcd. for C₁₇ H₂₁ N₆ O₅ SCl: 479.1 (M+Na), 457.1 (M+H). Found: 479.4,457.0.

EXAMPLE 323-(Phenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR56##

The title compound was prepared as in Example 30 starting withbenzenesulfonyl chloride (0.030 mL, 0.23 mmol). ¹ H NMR (300 MHz,DMSO-d₆) δ 11.00 (s, 1H), 9.34 (s, 1H), 8.43 (t, 1H, J=5.5 Hz), 7.82 (m,2H), 7.75 (br s, 4H), 7.60 (m, 3H), 7.26 (d, 1H, J=7.6 Hz), 6.09 (d, 1H,J=7.6 Hz), 4.61 (s, 2H), 3.79 (t, 2H, J=5.3 Hz), 3.38 (m, 2H), 2.19 (s,3H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix)calcd. for C₁₇ H₂₁ N₆ O₅ SCl: 445.1 (M+Na), 423.1 (M+H). Found: 445.1,423.0.

EXAMPLE 333-(3-Chlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR57##

The title compound was prepared as in Example 30 stating with3-chlorobenzenesulfonyl chloride (0.048 g, 0.23 mmol). ¹ H NMR (300 MHz,DMSO-d₆) δ 11.14 (br s, 1H), 9.63 (s, 1H), 8.45 (br s, 1H), 7.77 (m,6H), 7.55 (t, 1H, J=7.9 Hz), 7.29 (d, 1H, J=7.6 Hz), 6.11 (d, 1H, J=7.7Hz), 4.61 (s, 2H), 3.79 (t, 2H, J=5.3 Hz), 3.39 (m, 2H), 2.20 (s, 3H).Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd.for C₁₇ H₂₁ N₆ O₅ SCl: 479.1 (M+Na), 457.1 (M+H). Found: 479.0, 457.0.

EXAMPLE 343-(2-Methylsulfonylphenyl)sulfonylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR58##

The title compound was prepared in a manner analogous to Example 30. ¹H-NMR (300 MHz, DMSO-d₆) δ 8.32 (t, J=5.5 Hz, 1H), 8.21 (d, J=7.6 Hz,1H), 8.13 (d, J=7.5 Hz, H), 7.92 (m, 2H), 7.43 (d, J=7.4 Hz, 1H), 6.21(br s, 4H), 6.12 (d, J=7.5 Hz, 1H), 4.58 (s, 2H), 3.68 (t, J=5.4 Hz,2H), 3.47 (s, 3H), 3.29 (t, 2H, J=5.6 Hz), 2.17 (s, 3H). Mass spectrum(MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C₁₈ H₂₄ N₆O₅ S₂ : 501.1 (M+H), 523.1 (M+Na), 539.1 (M+K); Found: 501.1, 523.3,539.4.

EXAMPLE 353-(2-Naphthalenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR59## 1.3-(2-Naphthalenylsulfonyl)amino-6-methyl-1-{[N,N'-di(tert-butoxycarbonyl)][2-(guanidinooxyethyl)aminocarbonyl]}-2-pyridinone:

To a solution of 3-amino-6-methyl--{[N,N'-di(tert-butoxycarbonyl)][2-(guanidinooxyethyl)aminocarbonyl]}-2-pyridinone (0.050 g, 0.10 mmol),as prepared in step 3 of Example 30, in methylene chloride (2 mL) wasadded 2-naphthalenesulfonyl chloride (0.023 g, 0.10 mmol) anddiethylaminomethyl-polystyrene resin (0.033 g, ca. 0.10 mmol). Afterstirring 5 hours at ambient temperature, aminomethylated polystyreneresin (0.10 g, ca. 0.20 mmol) and more methylene chloride (2 mL) wereadded and the reaction was stirred an additional 16 hours. The resultingsuspension was poured onto a Waters silica Sep-Pak and eluted with10-50% ethyl acetate in methylene chloride, and the eluted productconcentrated in vacuo and used directly in the next step.

2.3-(2-Naphthalenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate:

The product of the preceding step was dissolved in methylene chloride(ca. 2 mL) and treated with neat trifluoroacetc acid (ca. 1 mL) atambient temperature for 4 hours. After evaporation, the crude productwas purified on a Waters silica Sep-Pak with 5% methanol in methylenechloride giving the title compound (0.007 g, 12%). ¹ H NMR (300 MHz,DMSO-d₆) δ 8.42 (m, 1H), 7.98 (m, 3H), 7.78 (dd, 1H, J=8.7 Hz, 1.9 Hz),7.63 (m, 2H), 7.55 (d, 1H, J=7.6 Hz), 6.19 (dd, 1H, J=7.7 Hz, 0.8 Hz),4.64 (s, 2H), 3.83 (t, 2H, J=5 Hz), 3.42 (t, 2H, J=5 Hz), 2.26 (s, 3H).Mass spectrum (LCMS, ESI) calcd. for C₁₇ H₂₁ N₆ O₅ SCl: 473.3 (M+H).Found: 473.2.

EXAMPLE 363-(4-Bromophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR60##

The title compound was prepared as in Example 35 starting with4-bromobenzenesulfonyl chloride (0.026 g, 0.10 mmol). ¹ H NMR (300 MHz,DMSO-d₆) δ 10.90 (s, 1H), 9.51 (s, 1H), 8.41 (t, 1H, J=5.6 Hz), 7.71 (m,8H), 7.28 (d, 1H, J=7.5 Hz), 6.11 (d, 1H, J=7.7 Hz), 4.60 (s, 2H), 4.11(m, 2H), 3.79 (t, 2H, J=5.3 Hz), 3.40 (m, 2H), 2.20 (s, 3H). Massspectrum (LCMS, ESI) calcd. for C₁₇ H₂₁ N₆ O₅ SBr: 503.0 (M+H). Found:503.0.

EXAMPLE 373-(4-Fluorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR61##

The title compound was prepared as in Example 35 starting with4-fluorobenzenesulfonyl chloride (0.020 g, 0.10 mmol). ¹ H NMR (300 MHz,DMSO-d₆) δ 10.90 (s, 1H), 9.41 (s, 1H), 8.41 (t, 1H, J=5.7 Hz), 7.87 (m,2H), 7.68 (br s, 4H), 7.36 (m, 2H), 7.28 (d, 1H, J=7.5 Hz), 6.10 (d, 1H,J=7.7 Hz), 4.60 (s, 2H), 4.10 (brd s, 2H), 3.79 (t, 2H, 5.3 Hz), 3.41(m, 2H), 2.20 (s, 3H). Mass spectrum (LCMS, ESI) calcd. for C₁₇ H₂₁ N₆O₅ SF: 441.2 (M+H). Found: 441.2.

EXAMPLE 383-(4-Iodophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR62##

The title compound was prepared as in Example 35 starting with4-iodobenzenesulfonyl chloride (0.030 g, 0.10 mmol). ¹ H NMR (300 MHz,DMSO-d₆) δ 10.95 (s, 1H), 9.48 (s, 1H), 8.42 (t, 1H, J=5.6 Hz), 7.91 (d,2H, J=8.6 Hz), 7.72 (br s, 4H), 7.56 (d, 2H, J=8.6 Hz), 7.27 (d, 1H,J=7.6 Hz), 6.10 (d, 1H, J=7.7 Hz), 4.60 (s, 2H), 3.80 (t, 2H, J=5.3 Hz),3.39 (m, 2H), 2.20 (s, 3H). Mass spectrum (LCMS, ESI) calcd. for C₁₇ H₂₁N₆ O₅ SI: 549.1 (M+H). Found: 549.0.

EXAMPLE 393-(4-Methoxyphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR63##

The title compound was prepared as in Example 35 starting with4-methoxybenzenesulfonyl chloride (0.021 g, 0.10 mmol). ¹ H NMR (300MHz, DMSO-d₆) δ 10.93 (s, 1H), 9.11 (s, 1H), 8.42 (m, 1H), 7.77 (d, 2H,J=9.0 Hz), 7.67 (m, 4H), 7.24 (d, 1H, J=7.5 Hz), 7.04 (d, 2H, J=8.9 Hz),6.08 (d, 1H, J=8.0 Hz), 4.61 (s, 2H), 3.79 (m, 5H), 3.40 (m, 2H), 2.19(s, 3H). Mass spectrum (LCMS, ESI) calcd. for C₁₈ H₂₄ N₆ O₆ S: 453.3(M+H). Found: 453.2.

EXAMPLE 403-(4-Methylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR64##

The title compound was prepared as in Example 35 starting with4-methylbenzenesulfonyl chloride (0.021 g, 0.10 mmol). ¹ H NMR (300 MHz,DMSO-d₆) δ 10.93 (s, 1H), 9.21 (s, 1H), 8.43 (t, 1H, J=5.5 Hz), 7.70 (m,6H), 7.33 (d, 2H, J=8.2 Hz), 7.24 (d, 1H, J=7.6 Hz), 6.08 (d, 1H, J=7.8Hz), 4.61 (s, 2H), 4.10 (m, 2H), 3.79 (t, 2H, J=5.3 Hz), 3.41 (m, 2H),2.35 (s, 3H), 2.19 (s, 3H). Mass spectrum (LCMS, ESI) calcd. for C₁₈ H₂₄N₆ O₅ S: 437.3 (M+H). Found: 437.2.

EXAMPLE 413-(3-Trifluoromethylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR65##

The title compound was prepared as in Example 35 starting with3-(trifluoromethyl)benzenesulfonyl chloride (0.025 g, 0.10 mmol). ¹ HNMR (300 MHz, DMSO-d₆) δ 10.86 (s, 1H), 9.76 (s, 1H), 8.40 (t, 1H, J=5.5Hz), 8.15 (s, 1H), 8.09 (d, 1H, J=8.0 Hz), 8.01 (d, 1H, J=7.9 Hz), 7.76(t, 1H, J=7.9 Hz), 7.67 (br s, 4H), 7.32 (d, 1H, J=7.5 Hz), 6.12 (d, 1H,J=7.7 Hz), 4.59 (s, 2H), 3.78 (t, 2H, J=5.3 Hz), 3.39 (m, 2H), 2.20 (s,3H). Mass spectrum (LCMS, ESI) calcd. for C₁₈ H₂₁ N₆ O₅ SF₃ : 491.2(M+H). Found: 491.1.

EXAMPLE 423-(3,4-dichlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl]aminocarbonylmethyl)-2-pyridinone trifluoroacetate ##STR66##

The title compound was prepared as in Example 35 starting with3,4-dichlorobenzenesulfonyl chloride (0.025 g, 0.10 mmol). ¹ H NMR (300MHz, DMSO-d₆) δ 10.90 (s, 1H), 9.73 (s, 1H), 8.41 (t, 1H, J=5.5 Hz),8.05 (d, 1H, J=2.1 Hz), 7.80 (d, 1H, J=8.4 Hz), 7.70 (m, 5H), 7.32 (d,1H, J=7.5 Hz), 6.13 (d, 1H, J=7.7 Hz), 4.60 (s, 2H), 3.79 (t, 2H, J=5.3Hz), 3.40 (m, 2H), 2.21 (s, 3H). Mass spectrum (LCMS, ESI) calcd. forC₁₇ H₂₀ N₆ O₅ SCl₂ : 491.2 (M+H). Found: 491.2.

EXAMPLE 433-(3-Chloro-4-fluorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR67##

The title compound was prepared as in Example 35 starting with3-chloro-4-fluorobenzenesulfonyl chloride (0.023 g, 0.10 mmol). ¹ H NMR(300 MHz, DMSO-d₆) δ 10.86 (s, 1H), 9.64 (s, 1H), 8.40 (t, 1H, J=5.6Hz), 8.05 (dd, 1H, J=6.9 Hz, 2.3 Hz), 7.79 (ddd, 1H, J=8.7 Hz, 4.5 Hz,2.3 Hz), 7.65 (brd s, 4H), 7.57 (t, 1H, J=8.9 Hz), 7.31 (d, 1H, J=7.5Hz), 6.12 (d, 1H, J=7.6 Hz), 4.60 (s, 2H), 3.79 (t, 2H, J=5.3 Hz), 3.40(m, 2H), 2.21 (s, 3H). Mass spectrum (LCMS, ESI) calcd. for C₁₇ H₂₀ N₆O₅ SFCl: 475.2 (M+H). Found: 475.2.

EXAMPLE 443-(4-Isopropylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR68##

The title compound was prepared as in Example 35 starting with4-isopropylbenzenesulfonyl chloride (0.022 g, 0.10 mmol). ¹ H NMR (300MHz, DMSO-d₆) δ 10.87 (s, 1H), 9.25 (s, 1H), 8.43 (t, 1H, J=5.5 Hz),7.77 (d, 2H, J=8.4 Hz), 7.66 (br s, 4H), 7.41 (d, 2H, J=8.4 Hz), 7.25(d, 1H, J=7.6 Hz), 6.09 (d, 1 H, J=7.7 Hz), 4.62 (s, 2H), 3.79 (t, 2H,J=5.3 Hz), 3.39 (m, 2H), 2.95 (p, 1H, J=6.9 Hz), 2.21 (s, 3H), 1.19 (d,6H, J=6.9 Hz). Mass spectrum (LCMS, ESI) calcd. for C₂₀ H₂₈ N₆ O₅ S:465.3 (M+H). Found: 465.2.

EXAMPLE 453-(3-Fluorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR69##

The title compound was prepared as in Example 35 starting with3-fluorobenzenesulfonyl chloride (0.020 g, 0.10 mmol). ¹ H NMR (300 MHz,DMSO-d₆) δ 10.86 (s, 1H), 9.58 (s, 1H), 8.41 (t, 1H, J=5.5 Hz), 7.59 (m,8H), 7.9 (d, 1H, J=7.6 Hz), 6.11 (d, 1H, J=7.6 Hz), 4.61 (s, 2H), 3.79(t, 2H, J=5.3 Hz), 3.41 (m, 2H), 2.20 (s, 3H). Mass spectrum (LCMS, ESI)calcd. for C₁₇ H₂₁ N₆ O₅ SF: 441.2 (M+H). Found: 441.1.

EXAMPLE 463-(3,5-Dichlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR70##

The title compound was prepared as in Example 35 starting with3,5-dichlorobenzenesulfonyl chloride (0.025 g, 0.10 mmol). ¹ H NMR (300MHz, DMSO-d₆) δ 0.86 (s, 1H), 9.85 (s, 1H), 8.41 (t, 1H, J=5.5 Hz), 7.93(t, 1H, J=1.8 Hz), 7.83 (d, 2H, J=1.8 Hz), 7.66 (br s, 4H), 7.33 (d, 1H,J=7.6 Hz), 6.14 (d, 1H, J=7.6 Hz), 4.62 (s, 2H), 3.79 (t, 2H, J=5.3 Hz),3.40 (m, 2H), 2.22 (s, 3H). Mass spectrum (LCMS, ESI) calcd. for C₁₇ H₂₀N₆ O₅ SCl₂ : 491.2 (M+H). Found: 491.2.

EXAMPLE 473-(3,4-Dimethoxyphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR71##

The title compound was prepared as in Example 35 starting with3,4-dimethoxybenzenesulfonyl chloride (0.023 g, 0.10 mmol). ¹ H NMR (300MHz, DMSO-d₆) δ 10.84 (s, 1H), 9.13 (s, 1H), 8.42 (t, 1H, J=5.6 Hz),7.65 (br s, 4H), 7.41 (m, 2H), 7.26 (d, 1H, J=7.5 Hz), 7.05 (d, 1H,J=9.1 Hz), 6.09 (d, 1H, J=7.9 Hz), 4.62 (s, 2H), 3.79 (m, 9H), 3.40 (m,2H), 2.19 (s, 3H). Mass spectrum (LCMS, ESI) calcd. for C₁₉ H₂₆ N₆ O₇ S:483.3 (M+H). Found: 483.1.

EXAMPLE 483-(2-Thienylsulfonyl)amino-6-methyl-1-[(2-guayzidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR72##

The title compound was prepared as in Example 35 starting with2-thiophenesulfonyl chloride (0.020 g, 0.11 mmol). ¹ H NMR (300 MHz,DMSO-d₆) δ 10.90 (s, 1H), 9.48 (s, 1H), 8.44 (t, 1H, J=5.4 Hz), 7.90(dd, 1H, J=5.0 Hz, 1.3 Hz), 7.69 (br s, 4H), 7.61 (dd, 1H, J=3.8 Hz, 1.3Hz), 7.33 (d, 1H, J=7.6 Hz), 7.12 (dd, 1H, J=4.9 Hz, 3.8 Hz), 6.14 (d,1H, J=7.7 Hz), 4.63 (s, 2H), 3.79 (t, 2H, J=5.3 Hz), 3.37 (m, 2H), 2.22(s, 3H). Mass spectrum (LCMS, ESI) calcd. for C₁₅ H₂₀ N₆ O₅ S₂ : 429.6(M+H). Found: 429.1.

EXAMPLE 493-(1-Naphthalenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR73##

The title compound was prepared as in Example 35 starting with1-naphthalenesulfonyl chloride (0.023 g, 0.10 mmol). ¹ H NMR (300 MHz,DMSO-d₆) δ 10.89 (s, 1H), 9.73 (s, 1H), 8.74 (m, 1H), 8.40 (t, 1H, J=5.6Hz), 8.21 (m, 2H), 8.08 (m, 1H), 7.67 (m, 7H), 7.18 (d, 1H, J=7.5 Hz),6.04 (d, 1H, J=8.0 Hz), 4.55 (s, 2H), 3.77 (t, 2H, J=5.3 Hz), 3.32 (m,2H), 2.15 (s, 3H). Mass spectrum (LCMS, ESI) calcd. for C₂₁ H₂₄ N₆ O₅ S:473.6 (M+H). Found: 473.2.

EXAMPLE 503-(2,4,6-Trimethylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR74##

The title compound was prepared as in Example 35 starting with2-mesitylenesulfonyl chloride (0.021 g, 0.10 mmol). ¹ H NMR (300 MHz,DMSO-d₆) δ 10.93 (s, 1H), 8.94 (s, 1H), 8.43 (t, 1H, J=5.5 Hz), 7.71(brd s, 4H), 7.12 (d, 1H, J=7.5 Hz), 6.99 (s, 2H), 6.07 (d, 1H, J=7.7Hz), 4.60 (s, 2H), 3.79 (t, 2H, J=5.3 Hz), 3.35 (q, 2H, J=5.2 Hz), 2.55(s, 6H), 2.23 (s, 3H), 2.18 (s, 3H). Mass spectrum (LCMS, ESI) calcd.for C₂₀ H₂₈ N₆ O₅ S: 465.6 (M+H). Found: 465.2.

EXAMPLE 513-(2-Methylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR75##

The title compound was prepared as in Example 35 starting witho-toluenesulfonyl chloride (0.019 g, 0.10 mmol). ¹ H NMR (300 MHz,DMSO-d₆) δ 10.89 (s, 1H), 9.27 (s, 1H), 8.43 (t, 1H, J=5.5 Hz), 7.81(dd, 1H, J=7.9 Hz, 1.2 Hz), 7.70 (m, 4H), 7.49 (td, 1H, J=7.5 Hz, 1.3Hz), 7.34 (dd, 2H, J=11 Hz, 8 Hz), 7.19 (d, 1H, J=7.5 Hz), 6.06 (d, 1H,J=7.7 Hz), 4.61 (s, 2H), 3.79 (t, 2H, J=5.2 Hz), 3.36 (m, 2H), 2.61 (s,3H), 2.18 (s, 3H). Mass spectrum (LCMS, ESI) calcd. for C₁₈ H₂₄ N₆ O₅ S:437.6 (M+H). Found: 437.1.

EXAMPLE 523-(2,5-Dimethylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR76##

The title compound was prepared as in Example 35 starting withp-xylene-2-sulfonyl chloride (0.022 g, 0.11 mmol). ¹ H NMR (300 MHz,DMSO-d₆) δ 10.92 (s, 1H), 9.19 (s, 1H), 8.45 (t, 1H, J=5.4 Hz), 7.68 (m,5H), 7.24 (m, 3H), 6.07 (d, 1H, J=7.6 Hz), 4.63 (s, 2H), 3.80 (t, 2H,J=5.2 Hz), 3.37 (m, 2H), 2.54 (s, 3H), 2.28 (s, 3H), 2.18 (s, 3H). Massspectrum (LCMS, ESI) calcd. for C₁₉ H₂₆ N₆ O₅ S: 451.6 (M+H). Found:451.1.

EXAMPLE 533-(2-Fluorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR77##

The title compound was prepared as in Example 35 starting with2-fluorobenzenesulfonyl chloride (0.020 g, 0.10 mmol). ¹ H NMR (300 MHz,CD₃ OD) δ 7.85 (t, 1H, J=7.5 Hz), 7.63 (m, 1H), 7.43 (d, 1H, J=7.7 Hz),7.27 (m, 2H), 6.17 (d, 1H, J=7.7 Hz), 4.70 (s, 2H), 3.94 (t, 2H, J=5.0Hz), 3.49 (t, 2H, J=5.0 Hz), 2.29 (s, 3H). Mass spectrum (LCMS, ESI)calcd. for C₁₇ H₂₁ N₆ O₅ SF: 441.5 (M+H). Found: 441.1.

EXAMPLE 543-(2-Chloro-6-methylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxypropyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR78##

The title compound was prepared as in Example 35 starting with2-chloro-6-methylbenzenesulfonyl chloride (0.022 g, 0.10 mmol). ¹ H NMR(300 MHz, DMSO-d₆) δ 10.98 (s, 1H), 9.05 (s, 1H), 8.44 (t, 1H, J=5.4Hz), 7.74 (br s, 4H), 7.46 (m, 2H), 7.34 (m, 1H), 7.20 (d, 1H, J=7.5Hz), 6.09 (d, 1H, J=7.8 Hz), 4.62 (s, 2H), 3.79 (t, 2H, J=5.3 Hz), 3.36(m, 2H), 2.63 (s, 3H), 2.19 (s, 3H). Mass spectrum (LCMS, ESI) calcd.for C₁₈ H₂₃ N₆ O₅ SCl: 471.0 (M+H). Found: 471.1.

EXAMPLE 553-(3-Bromo-6-methoxyphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR79##

The title compound was prepared as in Example 35 starting with5-bromo-2-methoxybenzenesulfonyl chloride (0.029 g, 0.10 mmol). ¹ H NMR(300 MHz, DMSO-d₆) δ 10.88 (s, 1H), 8.67 (s, 1H), 8.45 (t, 1H, J=5.6Hz), 7.79 (m, 2H), 7.68 (br s, 4H), 7.24 (d, 1H, J=7.5 Hz), 7.16 (d, 1H,J=8.9 Hz), 6.10 (d, 1H, J=7.8 Hz), 4.65 (s, 2H), 3.80 (m, 5H), 3.37 (m,2H), 2.19 (s, 3H). Mass spectrum (LCMS, ESI) calcd. for C₁₈ H₂₃ N₆ O₆SBr: 533.0 (M+H). Found: 533.0.

EXAMPLE 563-(3-Chloro-2-methylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR80##

The title compound was prepared as in Example 35 starting with3-chloro-2-methylbenzenesulfonyl chloride (0.023 g, 0.10 mmol). ¹ H NMR(300 MHz, DMSO-d₆) δ 10.89 (s, 1H), 9.65 (s, 1H), 8.43 (t, 1H, J=5.5Hz), 7. 81 (dd, 1H, J=7.9 Hz, 0.8 Hz), 7.69 (m, 5H), 7.33 (t, 1H, J=8.0Hz), 7.23 (d, 1H, J=7.6 Hz), 6.08 (d, H, J=7.7 Hz), 4.61 (s, 2H), 3.80(t, 2H, J=5.3 Hz), 3.36 (m, 2H), 2.65 (s, 3H), 2.19 (s, 3H). Massspectrum (LCMS, ESI) calcd. for C₁₈ H₂₃ N₆ O₅ SCl: 471.0 (M+H). Found:471.1

EXAMPLE 573-(2-Chloro-5-trifluoromethylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR81##

The title compound was prepared as in Example 35 starting with2-chloro-5-(trifluoromethyl)benzenesulfonyl chloride (0.027 g, 0.10mmol). ¹ H NMR (300 MHz, DMSO-d₆) δ 10.89 (s, 1H), 9.90 (s, 1H), 8.43(t, 1H, J=5.5 Hz), 8.31 (d, 1H J=1.8 Hz), 8.01 (dd, 1H, J=8.5 Hz, 2.0Hz), 7.90 (d, 1H, J=8.3 Hz), 7.69 (br s, 4H), 7.32 (d, 1H, J=7.6 Hz),6.13 (d, 2H, J=7.8 Hz), 4.64 (s, 2H), 3.79 (t, 2H, J=5.4 Hz), 3.35 (m,2H), 2.22 (s, 3H). Mass spectrum (LCMS, ESI) calcd. for C₁₈ H₂₀ N₆ O₅SClF₃ : 525.0 (M+H). Found: 525.1.

EXAMPLE 583-(2,4-Dichlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR82##

The title compound was prepared as in Example 35 starting with2,4-dichlorobenzenesulfonyl chloride (0.025 g, 0.10 mmol). ¹ H NMR (300MHz, DMSO-d₆) δ 10.89 (s, 1H), 9.46 (s, 1H), 8.43 (t, 1H, J=5.5 Hz),7.96 (d, 1H, J=8.6 Hz), 7.86 (d, 1H, J=2.1 Hz), 7.69 (br s, 4H), 7.57(dd, 1H, J=8.6 Hz, 2.1 Hz), 7.23 (d, 1H, J=7.6 Hz), 6.10 (d, 1H, J=7.7Hz), 4.62 (s, 2H), 3.80 (t, 2H, J=5.2 Hz), 3.37 (m, 2H), 2.21 (s, 3H).Mass spectrum (LCMS, ESI) calcd. for C₁₇ H₂₀ N₆ O₅ SCl₂ : 491.4 (M).Found: 491.1.

EXAMPLE 593-(4-Vinylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR83##

The title compound was prepared as in Example 35 starting withp-styrenesulfonyl chloride (0.021 g, 0.11 mmol). ¹ H NMR (300 MHz,DMSO-d₆) δ 10.92 (s, 1H), 9.34 (s, 1H), 8.42 (t, 1H, J=5.4 Hz), 7.79 (d,2H, J=8.4 Hz), 7.71 (br s, 4H), 7.62 (d, 2H, J=8.4 Hz), 7.26 (d, 1H,J=7.6 Hz), 6.78 (dd, 1H, J=17.7 Hz, 11.0 Hz), 6.09 (d, 1H, J=7.7 Hz),5.99 (d, 1H, J=17.6 Hz), 5.44 (d, 1H, J=11.1 Hz), 4.60 (s, 2H), 3.78 (t,2H, J=5.2 Hz), 3.35 (m, 2H), 2.19 (s, 3H). Mass spectrum (LCMS, ESI)calcd. for C₁₉ H₂₄ N₆ O₅ S: 449.6 (M+H). Found: 449.2.

EXAMPLE 603-(2-Butoxy-5-(1,1-dimethylpropyl)phenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR84##

The title compound was prepared as in Example 35 starting with2-(n-butoxy)-5-(2'-isopentyl)benzenesulfonyl chloride (0.033 g, 0.10mmol). ¹ H NMR (300 MHz, DMSO-d₆) δ 10.88 (brd s, 1H), 8.44 (br s, 1H),8.11 (s, 1H), 7.68 (m, 5H), 7.53 (dd, 1H, J=8.7 Hz, 2.4 Hz), 7.16 (d,1H, J=7.6 Hz), 7.10 (d, 1H, J=8.8 Hz), 6.03 (d, 1H, J=7.8 Hz), 4.66 (s,2H), 4.01 (t, 2H, J=6.4 Hz), 3.80 (t, 2H, J=5.2 Hz), 3.39 (m, 2H), 2.14(s, 3H), 1.76 (m, 2H), 1.57 (m, 2H), 1.47 (m, 2H), 1.22 (s, 6H), 0.94(t, 3H, J=7.4 Hz), 0.55 (t, 3H, J=7.3 Hz). Mass spectrum (LCMS, ESI)calcd. for C₂₆ H₄₀ N₆ O₆ S: 565.8 (M+H). Found: 565.2.

EXAMPLE 613-(3-Nitrophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR85##

The title compound was prepared as in Example 35 starting with3-nitrobenzenesulfonyl chloride (0.022 g, 0.10 mmol). ¹ H NMR (300 MHz,DMSO-d₆) δ 10.81 (br s, 1H), 9.85 (br s, 1H), 8.56 (t, 1H, J=1.9 Hz),8.43 (dd, 1H, J=8.3 Hz, 1.4 Hz), 8.34 (m, 1H), 8.18 (d, 1H, J=8.2 Hz),7.81 (t, 1H, J=8.0 Hz), 7.60 (br s, 4H), 7.34 (d, 1H, J=7.6 Hz), 6.13(d, 1H, J=7.7 Hz), 4.55 (s, 2H), 3.77 (m, 2H), 3.38 (m, 2H), 2.20 (s,3H). Mass spectrum (LCMS, ESI) calcd. for C₁₇ H₂₁ N₇ O₇ S: 468.2 (M+H).Found: 469.2.

EXAMPLE 623-(4-Chloro-3-nitrophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR86##

The title compound was prepared as in Example 35 starting with4-chloro-3-nitrobenzenesulfonyl chloride (0.026 g, 0.10 mmol). ¹ H NMR(300 MHz, DMSO-d₆) δ 10.90 (br s, 1H), 9.92 (br s, 1H), 8.44 (d, 1H,J=2.1 Hz), 8.38 (t, 1H, J=5.6 Hz), 8.02 (dd, 1H, J=8.5 Hz, 2.1 Hz), 7.92(d, 1H, J=8.5 Hz), 7.68 (br s, 4H), 7.36 (d, 1H, J=7.5 Hz), 6.15 (d, 1H,J=7.9 Hz), 4.58 (br s, 2H), 3.79 (t, 2H, J=5.4 Hz), 3.38 (m, 2H), 2.22(s, 3H). Mass spectrum (LCMS, ESI) calcd. for C₁₇ H₂₀ N₇ O₇ SCl: 502.0(M+H). Found: 502.1.

EXAMPLE 633-(4-Methylcarbonylaminophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR87##

The title compound was prepared as in Example 35 starting with4-(acetylamino)benzenesulfonyl chloride (0.023 g, 0.10 mmol). ¹ H NMR(300 MHz, DMSO-d₆) δ 10.86 (br s, 1H), 10.32 (s, 1H), 9.13 (s, 1H), 8.41(t, 1H, J=5.5 Hz), 7.76 (d, 2H, J=8.9 Hz), 7.69 (d, 2H, J=9.0 Hz), 7.63(br s, 4H), 7.23 (d, 1H, J=7.6 Hz), 6.08 (d, 1H, J=8.1 Hz), 4.61 (s,2H), 3.79 (t, 2H, J=5.4 Hz), 3.39 (m, 2H), 2.19 (s, 3H), 2.07 (s, 3H).Mass spectrum (LCMS, ESI) calcd. for C₁₉ H₂₅ N₇ O₆ S: 480.2 (M+H).Found: 480.2.

EXAMPLE 643-(4-tert-Butylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR88##

The title compound was prepared as in Example 35 starting with4-(tert-butyl)benzenesulfonyl chloride (0.023 g, 0.10 mmol). ¹ H NMR(300 MHz, DMSO-d₆) δ 10.85 (s, 1H), 9.27 (s, 1H), 8.43 (t, 1H, J=5.4Hz), 7.79 (d, 2H, 8.5 Hz), 7.65 (br s, 4H), 7.56 (d, 2H, J=8.6 Hz), 7.25(d, 1H, J=7.6 Hz), 6.09 (d, 1H, J=7.9 Hz), 4.62 (s, 2H), 3.79 (t, 2H,J=5.3 Hz), 3.40 (m, 2H), 2.19 (s, 3H), 1.28 (s, 9H). Mass spectrum(LCMS, ESI) calcd. for C₂₁ H₃₀ N₆ O₅ S: 479.3 (M+H). Found: 479.2.

EXAMPLE 653-(4-Trifluoromethylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR89##

The title compound was prepared as in Example 35 starting with4-(trifluoromethyl)benzenesulfonyl chloride (0.025 g, 0.10 mmol). ¹ HNMR (300 MHz, DMSO-d₆) δ 10.92 (s, 1H), 9.73 (s, 1H), 8.40 (t, 1H, J=5.5Hz), 8.01 (d, 2H, J=8.2 Hz), 7.91 (d, 2H, J=8.5 Hz), 7.69 (br s, 4H),7.31 (d, 1H, J=7.5 Hz), 6.12 (d, 1H, J=8.0 Hz), 4.59 (s, 2H), 3.78 (t,2H, J=5.3 Hz), 2.20 (s, 3H). Mass spectrum (LCMS, ESI) calcd. for C₁₈H₂₁ N₆ O₅ SF₃ : 491.2 (M+H). Found: 491.2.

EXAMPLE 663-(3-Cyanophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR90##

The title compound was prepared as in Example 35 starting with3-cyanobenzenesulfonyl chloride (0.020 g, 0.10 mmol). ¹ H NMR (300 MHz,DMSO-d₆) δ 10.91 (br s, 1H), 9.73 (br s, 1H), 8.40 (t, 1H, J=5.6 Hz),8.27 (t, 1H, J=1.6 Hz), 8.09 (dd, 1H, J=7.9 Hz, 1.6 Hz), 7.72 (m, 5H),7.33 (d, 1H, J=7.5 Hz), 6.12 (d, 1H, J=7.6 Hz), 4.59 (s, 2H), 4.10 (brs, 2H), 3.79 (t, 2H, J=5.3 Hz), 3.38 (m, 2H), 2.21 (s, 3H). Massspectrum (LCMS, ESI) calcd. for C₁₈ H₂₁ N₇ O₅ S: 448.2 (M+H). Found:449.2.

EXAMPLE 673-(4-Methylsulfonylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR91##

The title compound was prepared as in Example 35 starting with4-(methylsulfonyl)benzenesulfonyl chloride (0.024 g, 0.10 mmol). ¹ H NMR(300 MHz, DMSO-d₆) δ 10.87 (s, 1H), 9.78 (s, 1H), 8.40 (t, 1H, J=5.4Hz), 8.06 (s, 4H), 7.66 (br s, 4H), 7.32 (d, 1H, J=7.5 Hz), 6.12 (d, 1H,J=7.8 Hz), 4.59 (s, 2H), 3.78 (t, 2H, J=5.2 Hz), 3.40 (m, 2H), 3.28 (s,3H), 2.20 (s, 3H). Mass spectrum (LCMS, ESI) calcd. for C₁₈ H₂₄ N₆ O₇ S₂: 501.2 (M+H). Found: 501.1.

EXAMPLE 683-Dansylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR92##

The title compound was prepared as in Example 35 starting with dansylchloride (0.027 g, 0.10 mmol). ¹ H NMR (300 MHz, DMSO-d₆) δ 10.98 (s,1H), 9.66 (s, 1H), 8.39 (m, 3H), 8.20 (d, 1H, J=7.3 Hz), 7.75 (br s,4H), 7.58 (m, 2H), 7.25 (d, 1H, J=7.6 Hz), 7.16 (d, 1H, J=7.6 Hz), 6.04(d, 1H, J=7.7 Hz), 4.59 (s, 2H), 3.79 (t, 2H, J=5.1 Hz), 3.35 (m, 2H),2.82 (s, 6H), 2.15 (s, 3H). Mass spectrum (LCMS, ESI) calcd. for C₂₃ H₂₉N₇ O₅ S: 516.7 (M+H). Found: 516.2.

EXAMPLE 693-(Pentafluorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR93##

The title compound was prepared as in Example 35 starting withpentafluorobenzenesulfonyl chloride (0.028 g, 0.11 mmol). ¹ H NMR (300MHz, CD₃ OD) δ 7.55 (d, 1H, J=7.6 Hz), 6.27 (d, 1H, J=7.6 Hz), 4.68 (s,2H), 3.94 (t, 2H, J=5.0 Hz), 3.48 (t, 2H, J=5.0 Hz), 2.33 (s, 3H). Massspectrum (LCMS, ESI) calcd. for C₁₆ H₁₇ N₆ O₅ SF₅ : 513.5 (M+H). Found:513.1.

EXAMPLE 703-(2,5-Dichlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR94##

The title compound was prepared as in Example 35 starting with2,5-dichlorobenzenesulfonyl chloride (0.025 g, 0.10 mmol). ¹ H NMR (300MHz, DMSO-d₆) δ 10.89 (s, 1H), 9.68 (s, 1H), 8.44 (t, 1H, J=5.5 Hz),8.03 (d, 1H, J=2.1 Hz), 7.70 (m, 6H), 7.29 (d, 1H, J=7.6 Hz), 6.13 (d,1H, J=7.9 Hz), 4.65 (s, 2H), 3.80 (t, 2H, J=5.2 Hz), 3.39 (m, 2H), 2.22(s, 3H). Mass spectrum (LCMS, ESI) calcd. for C₁₇ H₂₀ N₆ O₅ SCl₂ : 491.0(M+H). Found: 491.1.

EXAMPLE 713-(2-Nitrophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR95##

The title compound was prepared as in Example 35 starting with2-nitrobenzenesulfonyl chloride (0.023 g, 0.10 mmol). ¹ H NMR (300 MHz,CD₃ OD) δ 8.00 (dd, 1H, J=7.6 Hz, 1.7 Hz), 7.91 (dd, 1H, J=7.8 Hz, 1.4Hz), 7.77 (m, 2H), 7.59 (d, 1H, J=7.6 Hz), 6.26 (dd, 1H, J=7.7 Hz, 0.8Hz), 4.70 (s, 2H), 3.92 (t, 2H, J=5.2 Hz), 3.48 (t, 2H, J=5.2 Hz), 2.31(s, 3H). Mass spectrum (LCMS, ESI) calcd. for C₁₇ H₂₁ N₇ O₇ S: 468.5(M+H). Found: 468.1.

EXAMPLE 723-Di(4-nitrophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR96##

The title compound was prepared as in Example 35 starting with4-nitrobenzenesulfonyl chloride (0.022 g, 0.10 mmol). ¹ H NMR (300 MHz,DMSO-d₆) δ 11.17 (s, 1H), 8.43 (d, 4H, J=8.9 Hz), 8.12 (d, 4H, J=8.9Hz), 7.84 (m, 4H), 7.60 (d, 1H, J=7.6 Hz), 6.34 (d, 1H, J=7.8 Hz), 4.63(s, 2H), 3.82 (m, 2H), 3.38 (m, 2H), 2.29 (s, 3H). Mass spectrum (LCMS,ESI) calcd. for C₂₁ H₂₄ N₈ O₁₁ S₂ : 653.6 (M+H). Found: 653.1.

EXAMPLE 733-(2,5-Dimethoxyphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR97##

The title compound was prepared as in Example 35 starting with2,5-dimethoxybenzenesulfonyl chloride (0.023 g, 0.10 mmol). ¹ H NMR (300MHz, CD₃ OD) δ 7.38 (d, 1H, J=7.7 Hz), 7.35 (d, 1H, J=2.8 Hz), 7.12 (dd,1H, J=9.0 Hz, 2.8 Hz), 7.04 (d, 1H, J=9.0 Hz), 6.13 (d, 1H, J=7.7 Hz),4.73 (s, 2H), 3.95 (t, 2H, J=5.0 Hz), 3.83 (s, 3H), 3.76 (s, 3H), 3.50(t, 2H, J=5.1 Hz), 2.26 (s, 3H). Mass spectrum (LCMS, ESI) calcd. forC₁₉ H₂₆ N₆ O₇ S: 483.6 (M+H). Found: 483.1.

EXAMPLE 743-(4-Propylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR98##

The title compound was prepared as in Example 35 starting with4-n-propylbenzenesulfonyl chloride (0.022 g, 0.10 mmol). ¹ H NMR (300MHz, CD₃ OD) δ 7.70 (m, 2H), 7.47 (d, 1H, J=7.6 Hz), 7.30 (d, 2H, J=7.9Hz), 6.19 (d, 1H, J=7.7 Hz), 4.70 (s, 2H), 3.93 (t, 2H, J=5.0 Hz), 3.48(t, 2H, J=5.0 Hz), 2.63 (t, 2H, J=7.6 Hz), 2.29 (s, 3H), 1.63 (sextet,2H, J=7.5 Hz), 0.92 (t, 3H, J=7.3 Hz). Mass spectrum (LCMS, ESI) calcd.for C₂₀ H₂₈ N₆ O₅ S: 465.6 (M+H). Found: 465.2.

EXAMPLE 753-(2-Methyl-5-nitrophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR99##

The title compound was prepared as in Example 35 starting with2-methyl-5-nitrobenzenesulfonyl chloride (0.024 g, 0.10 mmol). ¹ H NMR(300 MHz, DMSO-d₆) δ 11.04 (s, 1H), 9.87 (s, 1H), 8.45 (d, 1H, J=2.5Hz), 8.38 (t, 1H, J=5.5 Hz), 8.30 (dd, 1H, J=8.4 Hz, 2.5 Hz), 7.77 (brs, 4H), 7.65 (d, 1H, J=8.5 Hz), 7.32 (d, 1H, J=7.5 Hz), 6.12 (d, 1H,J=7.6 Hz), 4.55 (s, 2H), 3.78 (t, 2H, J=5.3 Hz), 3.32 (m, 2H), 2.75 (s,3H), 2.19 (s, 3H). Mass spectrum (LCMS, ESI) calcd. for C₁₈ H₂₃ N₇ O₇ S:482.5 (M+H). Found: 482.1.

EXAMPLE 763-(2-trifluoromethylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR100##

The title compound was prepared as in Example 35 starting with2-(trifluoromethyl)benzenesulfonyl chloride (0.025 g, 0.10 mmol). ¹ HNMR (300 MHz, DMSO-d₆) δ 10.95 (s, 1H), 9.50 (s, 1H), 8.45 (t, 1H, J=5.4Hz), 8.15 (m, 1H), 7.98 (m, 1H), 7.80 (m, 2H), 7.73 (br s, 4H), 7.28 (d,1H, J=7.6 Hz), 6.12 (d, 1H, J=7.7 Hz), 4.63 (s, 2H), 3.80 (t, 2H, J=5.2Hz), 3.36 (m, 2H), 2.21 (s, 3H). Mass spectrum (LCMS, ESI) calcd. forC₁₈ H₂₁ N₆ O₅ SF₃ : 491.5 (M+H). Found: 491.1.

EXAMPLE 773-(2,3-Dichlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR101##

The title compound was prepared as in Example 35 starting with2,3-dichlorobenzenesulfonyl chloride (0.023 g, 0.09 mmol). ¹ H NMR (300MHz, DMSO-d₆) δ 11.02 (s, 1H), 9.58 (s, 1H), 8.45 (t, 1H, J=5.5 Hz),7.97 (dd, 1H, J=8.0 Hz, 1.3 Hz), 7.91 (dd, 1H, J=8.1 Hz, 1.3 Hz), 7.77(br s, 4H), 7.50 (t, 1H, J=8.0 Hz), 7.24 (d, 1H, J=7.5 Hz), 6.10 (d, 1H,J=7.7 Hz), 4.63 (s, 2H), 3.80 (t, 2H, J=5.2 Hz), 3.36 (m, 2H), 2.21 (s,3H). Mass spectrum (LCMS, ESI) calcd. for C₁₇ H₂₀ N₆ O₅ SCl₂ : 491.0(M+H). Found: 491.1.

EXAMPLE 783-(2-Trifluoromethoxyphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR102##

The title compound was prepared as in Example 35 starting with2-(trifluoromethoxy)benzenesulfonyl chloride (0.025 g, 0.10 mmol). ¹ HNMR (300 MHz, DMSO-d₆) δ 10.93 (s, 1H), 9.31 (s, 1H), 8.44 (t, 1H, J=5.5Hz), 7.98 (dd, 1H, J=7.9 Hz, 1.6 Hz), 7.75 (m, 5H), 7.51 (m, 2H), 7.26(d, 1H, J=7.5 Hz), 6.11 (d, 1H, J=7.7 Hz), 4.63 (s, 2H), 3.80 (t, 2H,J=5.3 Hz), 3.36 (m, 2H), 2.21 (s, 3H). Mass spectrum (LCMS, ESI) calcd.for C₁₈ H₂₁ N₆ O₆ SF₃ : 507.5 (M+H). Found: 507.1.

EXAMPLE 793-(4-(3-Chloro-2-cyanophenoxy)phenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR103##

The title compound was prepared as in Example 35 starting with4(3-chloro-2-cyanophenoxy)benzenesulfonyl chloride (0.032 g, 0.10 mmol).¹ H NMR (300 MHz, DMSO-d₆) δ 10.95 (s, 1H), 9.43 (s, 1H), 8.43 (t, 1H,J=5.3 Hz), 7.89 (d, 2H, J=8.7 Hz), 7.72 (m, 5H), 7.57 (d, 1H, J=8.1 Hz),7.30 (m, 3H), 7.11 (d, 1H, J=8.4 Hz), 6.11 (d, 1H, J=7.7 Hz), 4.61 (s,2H), 3.79 (t, 2H, J=5.0 Hz), 3.34 (m, 2H), 2.20 (s, 3H). Mass spectrum(LCMS, ESI) calcd. for C₂₄ H₂₄ N₇ O₆ SCl: 574.0 (M+H). Found: 574.1.

EXAMPLE 803-(2-Chloro-4-fluorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR104##

The title compound was prepared as in Example 35 starting with2-chloro4-fluorobenzenesulfonyl chloride (0.023 g, 0.10 mmol). ¹ H NMR(300 MHz, DMSO-d₆) δ 10.92 (m, 1H), 9.34 (s, 1H), 8.44 (t, 1H, J=5.5Hz), 8.04 (dd, 1H, J=8.9 Hz, 5.9 Hz), 7.69 (m, 5H), 7.36 (m, 1H), 7.23(d, 1H, J=7.6 Hz), 6.10 (d, 1H, J=7.7 Hz), 4.63 (s, 2H), 3.80 (t, 2H,J=5.0 Hz), 3.37 (m, 2H), 2.20 (s, 3H). Mass spectrum (LCMS, ESI) calcd.for C₁₇ H₂₀ N₆ O₅ SClF: 475.0 (M+H). Found: 475.1.

EXAMPLE 813-(5-Chloro-2-methoxyphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR105##

The title compound was prepared as in Example 35 starting with5-chloro-2-methoxybenzenesulfonyl chloride (0.025 g, 0.11 mmol). ¹ H NMR(300 MHz, DMSO-d₆) δ 10.89 (s, 1H), 8.67 (s, 1H), 8.44 (t, 1H, J=5.4Hz), 7.68 (m, 6H), 7.23 (m, 2H), 6.10 (d, 1H, J=7.8 Hz), 4.65 (s, 2H),3.79 (m, 5H), 3.38 (m, 2H), 2.19 (s, 3H). Mass spectrum (LCMS, ESI)calcd. for C₁₈ H₂₃ N₆ O₆ SCl: 487.0 (M+H). Found: 487.1.

EXAMPLE 823-(2-Methoxy-5-methylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR106##

The title compound was prepared as in Example 35 starting with2-methoxy-5-methylbenzenesulfonyl chloride (0.023 g, 0.1 mmol). ¹ H NMR(300 MHz, DMSO-d₆) δ 10.88 (s, 1H), 8.45 (t, 1H, J=5.5 Hz), 8.29 (s,1H), 7.68 (br s, 4H), 7.58 (d, 1H, J=1.9 Hz), 7.40 (dd, 1H, J=8.5 Hz,1.9 Hz), 7.20 (d, 1H, J=7.6 Hz), 7.07 (d, 1H, J=8.5 Hz), 7.16 (d, 1H,J=8.9 Hz), 6.07 (d, 1H, J=7.7 Hz), 4.65 (s, 2H), 3.80 (m, 5H), 3.39 (m,2H), 2.27 (s, 3H), 2.17 (s, 3H). Mass spectrum (LCMS, ESI) calcd. forC₁₉ H₂₆ N₆ O₆ S: 467.6 (M+H). Found: 467.1.

EXAMPLE 833-(4-Phenylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR107##

The title compound was prepared as in Example 35 starting with4-phenylbenzenesulfonyl chloride (0.026 g, 0.10 mmol). ¹ H NMR (300 MHz,DMSO-d₆) δ 10.90 (s, 1H), 9.41 (s, 1H), 8.42 (t, 1H, J=5.4 Hz), 7.91 (d,2H, J=8.5 Hz), 7.83 (d, 2H, J=8.5 Hz), 7.71 (m, 6H), 7.46 (m, 3H), 7.31(d, 1H, J=7.6 Hz), 6.11 (d, 1H, J=7.7 Hz), 4.61 (s, 2H), 3.76 (t, 2H,J=5.0 Hz), 3.37 (m, 2H), 2.19 (s, 3H). Mass spectrum (LCMS, ESI) calcd.for C₂₃ H₂₆ N₆ O₅ S: 499.6 (M+H). Found: 499.2.

EXAMPLE 843-(5-Chlorothiophene-2-sulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR108##

The title compound was prepared as in Example 35 starting with5-chlorothiophene-2-sulfonyl chloride (0.023 g, 0.11 mmol). ¹ H NMR (300MHz, DMSO-d₆) δ 10.93 (s, 1H), 9.76 (s, 1H), 8.44 (t, 1H, J=5.5 Hz),7.67 (br s, 4H), 7.46 (d, 1H, J=4.1 Hz), 7.34 (d, 1H, J=7.5 Hz), 7.18(d, 1H, J=4.1 Hz), 6.16 (d, 1H, J=7.7 Hz), 4.64 (s, 2H), 3.80 (t, 2H,J=5.2 Hz), 3.38 (m, 2H), 2.24 (s, 3H). Mass spectrum (LCMS, ESI) calcd.for C₁₅ H₁₉ N₆ O₅ S₂ Cl: 463.0 (M+H). Found: 463.1.

EXAMPLE 853-(6-Chloronaphthalene-2-sulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR109##

The title compound was prepared as in Example 35 starting with2-(6-chloro)naphthalenesulfonyl chloride (0.026 g, 0.10 mmol). ¹ H NMR(300 MHz, DMSO-d₆) δ 10.87 (s, 1H), 9.53 (s, 1H), 8.53 (s, 1H), 8.38 (t,1H, J=5.5 Hz), 8.17 (m, 2H), 8.05 (d, 1H, J=8.8 Hz), 7.91 (dd, 1H, J=8.7Hz, 1.8 Hz), 7.68 (m, 5H), 7.32 (d, 1H, J=7.6 Hz), 6.09 (d, 1H, J=7.9Hz), 4.56 (s, 2H), 3.76 (t, 2H, J=5.2 Hz), 3.36 (m, 2H), 2.17 (s, 3H).Mass spectrum (LCMS, ESI) calcd. for C₂₁ H₂₃ N₆ O₅ SCl: 507.0 (M+H).Found: 507.1.

EXAMPLE 863-(6-Bromonaphthalene-2-sulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR110##

The title compound was prepared as in Example 35 starting with2-(6-bromo)naphthalenesulfonyl chloride (0.033 g, 0.11 mmol). ¹ H NMR(300 MHz, DMSO-d₆) δ 10.85 (s, 1H), 9.53 (s, 1H), 8.52 (s, 1H), 8.38 (t,1H, J=5.4 Hz), 8.33 (s, 1H), 8.11 (d, 1H, J=8.8 Hz), 8.04 (d, 1H, J=8.8Hz), 7.90 (dd, 1H, J=8.7 Hz, 1.6 Hz), 7.79 (dd, 1H, J=8.8 Hz, 1.8 Hz),7.66 (br s, 4H), 7.32 (d, 1H, J=7.6 Hz), 6.08 (d, 1H, J=7.7 Hz), 4.56(s, 2H), 3.76 (t, 2H, J=5.2 Hz), 3.39 (m, 2H), 2.17 (s, 3H). Massspectrum (LCMS, ESI) calcd. for C₂₁ H₂₃ N₆ O₅ SBr: 553.0 (M+H). Found:553.0.

EXAMPLE 873-(3-Bromophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR111##

The title compound was prepared as in Example 2 starting with3-bromobenzenesulfonyl chloride (0.128 g, 0.501 mmol). ¹ H-NMR (300 MHz,CD₃ OD) δ 7.98 (t, 1H, J=1.8 Hz), 7.75 (m, 2H), 7.50 (d, 1H, J=7.6 Hz),7.40 (t, 1H, J=8.0 Hz), 6.22 (d, 1H, J=7.6 Hz), 4.69 (s, 2H), 3.93 (t,2H, J=5.2 Hz), 3.49 (t, 2H, J=5.2 Hz), 2.31 (s, 3H). Mass spectrum(LCMS, ESI) calcd. for C₁₇ H₂₀ N₆ O₅ SBr: 501.5 (M+H). Found: 501.3.

EXAMPLE 883-(Quinoline-8-sulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR112##

The title compound was prepared in a manner analogous to Example 30. ¹H-NMR (300 Hz, CD₃ OD) δ 9.06-9.05 (m, 1H), 8.40-8.37 (m, 2H), 8.16 (d,J=7.0 Hz, 1H), 7.68-7.59 (m, 3H), 6.06 (d, J=7.6 Hz, 1H), 4.57 (s, 2H),3.71 (t, J=10.5 Hz, 2H), 3.34-3.33 (m, 2H), 2.17 (s, 3H). Mass spectrum(LCMS, ESI) calcd. for C₂₀ H₂₃ SO₅ N₇ : 474.4 (M+H); Found: 474.3.

EXAMPLE 893-(Quinoline-5-sulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR113##

The title compound was prepared in a manner analogous to Example 30. ¹H-NMR (300 Hz, CD₃ OD) δ 9.32 (br s, 1H), 8.62-8.30 (m, 4H), 7.73-7.70(m, 1H), 7.28 (br s, 1H), 6.12 (d, J=6.6 Hz, 1H), 4.62 (s, 2H), 3.64 (brs, 2H), 3.37 (br s, 2H), 2.23 (s, 3H). Mass spectrum (LCMS, ESI) calcd.for C₂₀ H₂₃ SO₅ N₇ : 474.4 (M+H); Found: 474.3.

EXAMPLE 903-(1-Methylimidazole-4-sulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR114##

The title compound was prepared in a manner analogous to Example 30. ¹H-NMR (300 Hz, CD₃ OD) δ 7.73 (br s, 2H), 7.36 (d, 1H), 6.37-6.35 (m,2H), 4.89 (s, 2H), 3.86 (bs, 2H), 3.43 (br s, 2H), 3.34 (s, 3H), 2.34(s, 3H). Mass spectrum (LCMS, ESI) calcd. for C₁₅ H₂₂ SO₅ N₈ : 427.4(M+H); Found 427.4.

EXAMPLE 913-(3-Methylquinoline-8-sulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR115##

The title compound was prepared in a manner analogous to Example 30. ¹H-NMR (300 Hz, CD₃ OD) δ 8.89 (d, J=2.2 Hz, 1H), 8.30 (dd, J=1.3, 7.3Hz, 1H), 8.17-8.16 (m, 1H), 8.10 (dd, J=1.3, 7.0 Hz, 1H), 7.62 (t, J=7.4Hz, 1H), 7.50 (d, J=7.6 Hz, 1H), 6.09 (d, J=7.1 Hz, 1H), 4.59 (s, 2H),3.90 (t, J=5.1 Hz, 2H), 2.55 (s, 3H), 2.19 (S, 3H). Mass spectrum (LCMS,ESI) calcd. for C₂₁ H₂₆ SO₅ N₇ : 488.5 (M+H); Found 488.5.

EXAMPLE 923-(2-Pyridinylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR116## 1.3-(2-Pyridinylsulfonyl)amino-6-methyl-1-{[N,N'-di(tert-butoxycarbonyl)][2-(guanidinooxyethyl)aminocarbonylmethyl]}-2-pyridinone

To a stirred reaction mixture of 2-mercaptopyridine (500 mg, 4.5 mmol)and 1N HCl (5 mL) at 0° C., was bubbled in chlorine gas for 1 hr. Thereaction mixture was extracted with methylene chloride (3×50 mL), dried(Na₂ SO₄), and concentrated to yield a clear oil, which was usedimmediately. N,N-Dimethylaminopyridine (200 mg) is added to a stirredreaction mixture of 2-pyridinesulfonyl chloride (50 mg, 0.178 mmol), and3-amino-6-methyl-1-{[N,N'-di(tert-butoxycarbonyl)][3-(guanidinooxyethyl)aminocarbonyl]}-2-pyridinone (78 mg, 0.162 mmol),as prepared in step 3 of Example 30, in methylene chloride (2 mL).Reaction mixture was stirred 16 hrs, concentrated in vacuo and purifiedon silica gel column chromatrography (4% methanol/96% methylenechloride) to give the title compound as a white solid (34 mg, 30%yield). Mass spectrum (LCMS, ESI) calcd. for C₂₆ H₃₇ SO₉ N₇ : 624.6(M+H); Found 624.1.

2.3-(2-Pyridinylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

To a stirred reaction mixture of3-(2-pyridinylsulfonyl)amino-6-methyl-1-{[N,N'-di(tert-butoxycarbonyl)][2-(guanidinooxyethyl)aminocarbonylmethyl]}-2-pyridinone (34 mg, 0.055mmol) in methylene chloride (1 mL) was added trifluoroacetic acid (0.5mL). The reaction was stirred at ambient temperature for 2 hr, and waspurified on a Waters Sep-Pak (2 g) (10% methanol/89% methylene chloride,1% trifluoroacetic acid), to yield the title compound as a yellow solid(9 mg, 39% yield). ¹ H-NMR (300 Hz, CD₃ OD) δ 8.92 (s, 1H), 8.70 (br s,1H), 8.15 (d, J=8.0 Hz, 1H), 7.57-7.49 (m, 2H), 6.23 (d, J=7.6 Hz, 1H),4.67 (s, 1H), 3.91 (t, J=5.0 Hz, 2H), 3.47 (t, J=5.0 Hz, 2H), 2.30 (s,3H). Mass spectrum (LCMS, ESI) calcd. for C₁₆ H₂₁ SO₅ N₇ : 424.4 (M+H);Found 424.1.

EXAMPLE 933-(3-Pyridinylsulfonyl)amino-6-methyl-1-[(2-guanidinooxypropyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR117##

The title compound was prepared in a manner analogous to Example 92. ¹H-NMR (300 Hz, CD₃ OD) δ 8.92 (br s, 1H), 8.70 (br s, 1H), 8.16 (d,J=8.0 Hz, 1H), 7.57-7.49 (m, 2H), 6.23 (d, J=7.6 Hz, 1H), 4.67 (s, 2H),3.9 (t, J=5.0 Hz, 2H), 3.47 (t, J=5.0 Hz, 2H), 2.30 (s, 3H). Massspectrum (LCMS, ESI) calcd. for C₁₆ H₂₁ SO₅ N₇ : 424.4 (M+H); Found424.1.

EXAMPLE 943-(4-Ethylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR118##

The title compound was prepared as in Example 2 starting with4-ethylbenzenesulfonyl chloride (0.102 g, 0.498 mmol). ¹ H NMR (300 MHz,CD₃ OD) δ 7.71 (d, 2H, J=8.4 Hz), 7.47 (d, 1H, J=7.6 Hz), 7.31 (d, 2H,J=8.4 Hz), 6.19 (dd, 1H, J=7.7 Hz, 0.5 Hz), 4.71 (s, 2H), 3.93 (t, 2H,J=5.1 Hz), 3.48 (t, 2H, J=5.1 Hz), 2.68 (q, 2H, J=7.6 Hz), 2.29 (s, 3H),1.22 (t, 3H, J=7.6 Hz). Mass spectrum (LCMS, ESI) calcd. for C₁₉ H₂₅ N₆O₅ S: 450.5 (M+H). Found: 451.2.

EXAMPLE 953-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)-N-methylaminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR119##

The title compound was prepared from 2-(methylamino)ethanol using theprocedures in steps 6-10 of Example 1 and steps 5 & 6 of Example 2. ¹H-NMR (300 Hz, CD₃ OD) δ 7.65 (m, 2H), 7.35 (m, 2H), 6.16 (m, 1H),5.04-5.01 (m, 2H), 3.97-3.92 (m, 2H), 3.69-3.63 (m, 2H) 3.29 (s, 3H),2.36 (s, 3H). Mass spectrum (LCMS, ESI) calcd. for C₁₉ H₂₆ SO₅ N₆ :451.4 (M+H); Found: 451.4.

EXAMPLE 963-(3-Methylphenylsulfonyl)amino-6-isopropyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonehydrochloride ##STR120## 1. 3-Cyano-6-isopropyl-2(1H)-pyridinone:

A solution of 3-cyano-6-methyl-2(1H)-pyridinone (10.0 g, 74.6 mmol) inanhydrous tetrahydrofuran (100 mL) was cooled to -78° C. under nitrogenand reacted slowly with lithium diisopropylamide solution (40 mL of 1.4M and 85 mL of 2.0 M, 226 mmol total) via syringe. After warming to 0°C. and stirring 2 hours, methyl iodide (10 mL, 160 mmol) was added andthe reaction stirred 18 hours at ambient temperature. The reaction waspoured into 0.67 N NaOH (300 mL), the phases separated, the aqueouslayer washed with diethyl ether, and the combined organic layersextracted with water. The combined aqueous layers were acidified to pH 4with 6 N HCl and extracted with methylene chloride, and the methylenechloride layer was washed with brine, dried over Na₂ SO₄, and filtered.The filtrate was concentrated in vacuo and the residue purified by flashcolumn chromatography (1:1 methylene chloride:ethyl acetate) giving thetitle compound as a light yellow solid (2.15 g, 18%). ¹ H NMR (300 MHz,CDCl₃) δ 13.25 (br s, 1H), 7.84 (d, 1H, J=7.5 Hz), 6.23 (d, 1H, J=7.5Hz), 3.00 (septet, 1H, J=7.0 Hz), 1.36 (s, 3H), 1.34 (s, 3H). Alsorecovered from the column was the mono-methylated side-product3-cyano-6-ethyl-2(1H)pyridinone (5.50 g, 50%). which was used to makethe title compound in Example 97. ¹ H NMR (300 MHz, CDCl₃) δ 7.84 (d,J=7.5 Hz, 1H), 6.23 (d, J=7.4 Hz, 1H), 2.76 (q, J=7.6 Hz, 2H), 1.35 (t,J=7.5 Hz, 3H).

2. 3-Carboxy-6-isopropyl-2(1H)-pyridinone:

3-Cyano-6-isopropyl-2(1H)-pyridinone (2.92 g, 18.0 mmol), as prepared inthe preceding step, was dissolved in hot 50% v/v sulfuric acid (45 mL)and refluxed for 3 hours. After cooling to ambient temperature, thereaction mixture was poured into 200 mL of ice water and the resultingprecipitate collected by filtration, washed with water, then air andvacuum dried giving the title compound (2.83 g, 87%) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 13.67 (s, 1H), 12.75 (br s, 1H), 8.56 (d, 1H,J=7.5 Hz), 6.56 (dd, 1H, J=7.6 Hz, 1.6 Hz), 3.02 (septet, 1H, J=6.9 Hz),1.41 (s, 3H), 1.39 (s, 3H).

3. 3-(Benzyloxycarbonyl)amino-6-isopropyl-2(1H)-pyridinone:

3-Carboxy-6-isopropyl-2(1H)-pyridinone (2.82 g, 15.6 mmol), as preparedin the preceding step, diphenylphosphoryl azide (3.50 mL, 16.2 mmol),and triethylamine (2.30 mL, 16.5 mmol) were refluxed in 1,4-dioxane (100mL) for 16 hours. Benzyl alcohol (1.65 mL, 15.9 mmol) and additionaltriethylamine (2.40 mL, 17.2 mmol) were added and the reaction refluxedanother 24 hours. After concentrating the reaction mixture in vacuo, theresidue was dissolved in methylene chloride, washed with pH 1 brine,saturated NaHCO₃, and pH 7 brine, dried over MgSO₄, and filtered. Theevaporated filtrate was then purified by flash column chromatography(gradient elution, 10% to 25% ethyl acetate in methylene chloride)giving the title compound as a light yellow solid (1.10 g, 25%). ¹ H NMR(300 MHz, CDCl₃) δ 11.61 (br s, 1H), 8.05 (br d, 1H, J=7.2 Hz), 7.67 (s,1H), 7.39 (m, 5H), 6.08 (d, 1H, J=7.7 Hz), 5.21 (s, 2H), 2.80 (septet,1H, J=6.9 Hz), 1.28 (s, 3H), 1.26 (s, 3H).

4.3-(Benzyloxycarbonyl)amino-6-isopropyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone:

3-(Benzyloxycarbonyl)amino-6-isopropyl-2(1 H)-pyridinone (1.10 g, 3.84mmol), as prepared in the preceding step, was dissolved in anhydroustetrahydrofuran (30 mL) and cooled to 0° C. under nitrogen. A 1.0 Msolution of lithium bis(trimethylsilyl)amide in hexanes (4.2 mL, 4.2mmol) was added via syringe and the reaction stirred for one hour.tert-Butylbromoacetate (0.70 mL, 4.3 mmol) was then added via syringeand the reaction stirred at ambient temperature for 16 hours. Afterconcentration in vacuo, the crude product was purified by flash columnchromatography (1:1 hexane:ethyl acetate) giving the title compound as apale yellow oil (1.38 g, 90%). ¹ H NMR (300 MHz, CDCl₃) δ 8.00 (br d,1H, J=7.8 Hz), 7.78 (s, 1H), 7.36 (m, 5H), 6.15 (d, 1H, J=7.9 Hz), 5.19(s, 2H), 4.79 (s, 2H), 2.72 (m, 1H), 1.46 (s, 9H), 1.26 (s, 3H), 1.23(s, 3H). Mass spectrum (MALDI-TOF, gentisic acid matrix) calcd. for C₂₂H₂₈ N₂ O₅ : 423.2 (M+Na). Found: 423.6.

5. 3-Amino-6-isopropyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone:

3-(Benzyloxycarbonyl)amino-6-isopropyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone(1.35, 3.37 mmol), as prepared in the preceding step, and 10% palladium(0) on activated carbon (0.12 g) were dissolved in methanol (50 mL),degassed, backfilled with nitrogen, and stirred under hydrogen gas atambient pressure and temperature for 2 hours. The reaction mixture wasthen filtered through Celite and the filtrate evaporated giving thetitle compound as a golden oil, which was used without furtherpurification.

6.3-(3-Methylphenylsulfonyl)amino-6-isopropyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone:

3-Amino-6-isopropyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone (assumedto be 3.37 mmol), as prepared in the preceding step, andN-methylmorpholine (1.0 mL, 9.1 mmol) were dissolved in methylenechloride (20 mL) and cooled to 0° C. A solution of m-toluenesulfonylchloride (0.67 g, 3.5 mmol) in methylene chloride (5 mL) was added andthe reaction stirred at ambient temperature for 16 hours. Afterevaporation in vacuo, the crude product was dissolved in methylenechloride, washed with 10% aqueous citric acid, saturated NaHCO₃, andbrine, dried over MgSO₄, and filtered. The evaporated filtrate gave thetitle compound (1.24 g, 88%) as a tan solid. ¹ H NMR (300 MHz, CDCl₃) δ7.65 (m, 2H), 7.58 (br s, 1H), 7.46 (d, 1H, J=7.8 Hz), 7.33 (m, 2H),6.08 (d, 1H, J=7.9 Hz), 4.69 (s, 2H), 2.67 (m, 1H), 2.38 (s, 3H), 1.41(s, 9H), 1.22 (s, 3H), 1.19 (s, 3H).

7.3-(3-Methylphenylsulfonyl)amino-6-isopropyl-1-(carboxymethyl)-2-pyridinone:

3-(3-Methylphenylsulfonyl)amino-6-isopropyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone(1.24 g, 2.95 mmol), as prepared in the preceding step, was dissolved inmethylene chloride (20 mL) and reacted with trifluoroacetic acid (8 mL)at ambient temperature for 2 hours. After evaporation in vacuo, thecrude product was dissolved in methylene chloride, washed with pH 7buffer and brine, dried over MgSO₄, and filtered. Evaporation of thefiltrate gave the title compound (0.72 g, 67%) as a light yellow solid.Mass spectrum (LCMS, ESI) calcd. for C₁₇ H₂₀ N₂ O₅ S: 365.4 (M+H).Found: 365.1.

8.3-(3-Methylphenylsulfonyl)amino-6-isopropyl-1-{[N,N'-di(tert-butoxycarbonyl)]-2-(guanidinyloxyethyl)aminocarbonylmethyl}-2-pyridinone:

3-(3-Methylphenylsulfonyl)amino-6-isopropyl-1-(carboxymethyl)-2-pyridinone(0.71 g, 1.95 mmol), as prepared in the preceding step, Castro's reagent(BOP, 0.905 g, 2.05 mmol), and [N,N'-di(tert-butoxycarbonyl)]2-aminoethoxyguanidine (0.710 g, 2.00 mmol), as prepared in step 4 ofExample 2, were dissolved in methylene chloride (40 mL) and reacted withtiethylamine (0.75 mL, 5.4 mmol) at ambient temperature for 3 days.After concentration in vacuo, the crude product was dissolved inmethylene chloride, washed with 10% aqueous citric acid, saturatedNaHCO₃, and brine, dried over Na₂ SO₄, and filtered. The evaporatedfiltrate was purified by flash column chromatography (5% methanol inmethylene chloride) giving the title compound as a light yellow solid(0.70 g, 54%). ¹ H NMR (300 MHz, CDCl₃) δ 9.15 (s, 1H), 8.34 (br t, 1H,J=5.0 Hz), 7.67 (m, 3H), 7.59 (s, 1H), 7.40 (d, 1H, J=7.9 Hz), 7.34 (m,2H), 6.06 (d, 1H, J=7.9 Hz), 4.86 (s, 2H), 4.09 (m, 2H), 3.58 (dd, 2H,J=8.8 Hz, 5.0 Hz), 2.86 (m, 1H), 2.38 (s, 3H), 1.52 (s, 9H), 1.47 (s,9H), 1.20 (s, 3H), 1.17 (s, 3H).

9.3-(3-Methylphenylsulfonyl)amino-6-isopropyl-1-{2-(guanidinyloxyethyl)aminocarbonylmethyl}-2-pyridinonehydrochloride:

3-(3-Methylphenylsulfonyl)amino-6-isopropyl-1-{[N,N'-di(tert-butoxycarbonyl)]-2-(guanidinyloxyethyl)aminocarbonylmethyl}-2-pyridinone(0.70 g, 1.05 mmol), as prepared in the preceding step, was dissolved inmethylene chloride (10 mL) and reacted with trifluoroacetic acid (5 mL)at ambient temperature for 2.5 hours. The evaporated crude product waslyophilized from acetonitrile/water, purified by flash columnchromatography (gradient elution, 10% to 20% methanol in methylenechloride saturated with gaseous ammonia), and evaporated from 4 N HCl inethanol (20 mL) giving the title compound as a white solid (0.36 g,68%). ¹ H NMR (300 MHz, DMSO-d₆) δ 10.91 (br s, 1H), 9.34 (brd s, 1H),8.49 (t, 1H, J=5.5 Hz), 7.65 (m, 6H), 7.43 (m, 2H), 7.28 (d, 1H, J=7.8Hz), 6.14 (d, 1H, J=7.9 Hz), 4.69 (s, 2H), 3.79 (t, 2H, J=5.3 Hz), 3.38(m, 2H), 2.79 (m, 1H), 2.35 (s, 3H), 1.13 (s, 3H), 1.08 (s, 3H). Massspectrum (LCMS, ESI) calcd. for C₂₀ H₂₈ N₆ O₅ S: 465.5 (M+H). Found:465.1.

EXAMPLE 973-(3-Methylphenylsulfonyl)amino-6-ethyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR121##

The title compound was prepared in a manner analogous to Example 96. ¹H-NMR (300 MHz, DMSO-d₆) δ 10.92 (s, 1H), 9.32 (s, 1H), 8.42 (t, J=5.6Hz, 1H) 7.71 (br s, 4H), 7.67 (s, 1H), 7.64 (t, J=3.0 Hz, 1H), 7.42 (d,J=6.1 Hz, 1H), 7.29 (d, J=7.7 Hz, 1H), 6.07 (d, J=7.8 Hz, 1H), 4.62 (s,2H), 3.79 (t, J=5.4 Hz, 2H), 3.34 (t, J=5.6 Hz, 2H), 2.24 (s, 3H). Massspectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₁₉ H₂₆ N₆ O₅ S: 451.2 (M+H), 473.2 (M+Na); Found: 451.1, 473.0.

EXAMPLE 983-(3-Methylphenylsulfonyl)amino-6-propyl-1-{2-(guanidinyloxyethyl)aminocarbonylmethyl}-2-pyridinonetrifluoroacetate ##STR122##

The title compound was prepared in a manner analogous to Example 96. ¹ HNMR (300 MHz, DMSO-d₆) δ 11.25 (s, 1H), 9.32 (s, 1H), 8.48 (t, 1H, J=5.5Hz), 7.91 (br s, 4H), 7.63 (m, 2H), 7.42 (m, 2H), 7.29 (d, 1H, J=7.7Hz), 6.07 (d, 1H, J=7.7 Hz), 4.61 (s, 2H), 3.81 (t, 2H, J=5.3 Hz), 3.35(m, 2H), 2.45 (t, 2H, J=7.7 Hz), 2.35 (s, 3H), 1.50 (sextet, 2H, J=7.5Hz), 0.89 (t, 3H, J=7.3 Hz). Mass spectrum (LCMS, ESI) calcd. for C₂₀H₂₈ N₆ O₅ S: 465.5 (M+H). Found: 465.1.

EXAMPLE 993-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-N"-methylguanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonehydrochloride ##STR123##

A solution of3-(3-methylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonehydrochloride (0.2 g, 0.42 mmol), as prepared in step 5 of Example 5, inN,N-dimethylformamide (6 mL) was treated with sodium bicarbonate (0.78g, 9.2 mmol) followed by methyl iodide (0.32 mL, 5 mmol) and allowed tostir at room temperature for 2.5 h. The reaction mixture was evaporatedunder high vacuum and the residue was treated with brine and adjusted topH 1 with 1M HCl. The insoluble material was collected by filtration.The aqueous layer was extracted with methylene chloride (5×). Thecombined methylene chloride extracts were extracted with saturatedsodium bicarbonate (2×). The combined aqueous bicarbonate extracts wereadjusted to pH 1 with 1M HCl. The insoluble material was collected byfiltration and combined with the previous solids from the acidic brinetreatment. The solids were dried under high vacuum overnight, thentreated with methanol and filtered to remove insoluables. Evaporation ofthe filtrate gave the title compound as a white solid (154 mg, 75%). ¹H-NMR (300 MHz, DMSO-d₆) δ 9.30 (s, 1H), 8.85 (t, J=5.3 Hz, 1H), 8.14(s, 4H), 7.61-7.66 (m, 2H), 7.39-7.44 (m, 2H), 7.23 (d, J=7.6 Hz, 1H),6.08 (d, J=8.2 Hz, 1H), 4.67 (m, 2H), 3.91 (t, J=5.1 Hz, 2H), 3.39 (m,2H), 3.28 (s, 3H), 2.35 (s, 3H), 2.19 (s, 3H). Mass spectrum (LCMS, ESI)clacd. for C₁₉ H₂₆ N₆ O₅ S: 451 (M+H); Found: 451.2. MS-MS of 451.2 peakgave 408.9 (M--C(═NH)NH).

EXAMPLE 1003-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-N"-ethylguanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonehydrochloride ##STR124##

The title compound was prepared in a manner analogous to Example 99. ¹ HNMR (300 MHz, DMSO-d₆) δ 9.26 (br s, 1H), 8.55 (t, 1H, J=5.2 Hz), 7.95(br s, 4H), 7.64 (m, 2H), 7.42 (m, 2H), 7.24 (d, 1H, J=7.5 Hz), 6.08 (d,1H, J=7.7 Hz), 4.63 (s, 2H), 3.87 (br t, 2H, J=5.0 Hz), 3.66 (q, 2H,J=6.9 Hz), 2.35 (s, 3H), 2.19 (s, 3H), 1.09 (t, 3H, J=6.9 Hz). Massspectrum (LCMS, ESI) calcd. for C₂₀ H₂₈ N₆ O₅ S: 465.5 (M+H). Found:465.1. MS-MS of 465.1 peak gave 423.0 (M--C(═NH)NH).

EXAMPLE 1013-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-N"-benzylguanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonehydrochloride ##STR125##

The title compound was prepared in a manner analogous to Example 99.Mass spectrum (LCMS, ESI) calcd. for C₂₅ H₃₀ N₆ O₅ S: 527.6 (M+H).Found: 527.0. MS-MS of 527.0 peak gave 485.0 (M--C(═NH)NH).

EXAMPLE 1023-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-N"-butylguanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonehydrochloride ##STR126##

The title compound was prepared in a manner analogous to Example 99. ¹ HNMR (300 MHz, CDCl₃ /CD₃ OD) δ 7.64 (m, 2H), 7.42 (d, 1H, J=7.7 Hz),7.36 (m, 2H), 6.11 (d, 1H, J=7.7 Hz), 4.70 (s, 2H), 3.58 (t, 2H, J=7.3Hz), 3.49 (t, 2H, J=4.9 Hz), 2.39 (s, 3H), 2.30 (s, 3H), 1.64 (m, 2H),1.36 (m, 4H), 0.95 (t, 3H, J=7.2 Hz). Mass spectrum (LCMS, ESI) calcd.for C₂₂ H₃₂ N₆ O₅ S: 493.6 (M+H). Found: 493.3. MS-MS of 493.3 peak gave452.0 (M--C(═NH)NH).

EXAMPLE 1033-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-N-methylguanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR127## 1. [N,N'-Di(tert-butoxycarbonyl)]2-(benzyloxycarbonylamino)ethoxy-N-methylguanidine

To a solution of [N,N'-di(tert-butoxycarbonyl)]2-(benzyloxycarbonylamino)ethoxyguanidine (905 mg, 2.0 mmol), asprepared in step 3 of Example 2, methanol (121 μL, 3.0 mmol) andtriphenylphosphine (790 mg, 3.0 mmol) in tetrahydrofuran (30 mL) wasadded diethyl azodicarboxylate (520 mg, 3.0 mmol). The mixture wasstirred at ambient temperature overnight. Ethyl acetate (50 mL) wasadded, washed with saturated NaHCO₃ (40 mL), brine (2×40 mL) and driedover Na₂ SO₄. After evaporating the solvent, the residue was purified byflash chromatography (0-4% ethyl acetate in methylene chloride) to givethe title compound as a white solid (385 mg, 41%). ¹ H-NMR (300 MHz,CDCl₃) δ 7.36 (m, 5H), 5.30 (br s, 1H), 5.11 (s, 2H), 4.12 (t, J=5.0 Hz,2H), 3.50 (t, J=5.0 Hz, 2H), 3.07 (s, 3H), 1.48 (s, 9H), 1.43 (s, 9H).

2. [N,N'-Di(tert-butoxycarbonyl)] 2-aminoethoxy-N-methylguanidine

A mixture of [N,N'-di(tert-butoxycarbonyl)]2-(benzyloxycarbonylamino)ethoxy-N-methylguanidine (700 mg, 1.5 mmol),as prepared in the preceding step, 10% Pd/C (70 mg) in methanol (20 mL)and chloroform (5 mL) was hydrogenated under hydrogen (balloon) for 1 h.The catalyst was removed by filtration through Celite, the filtrate wasconcentrated in vacuo. The residue was purified by flash chromatography(95:5 methylene chloride:methanol saturated with ammonia) to give thetitle compound as a colorless foam (250 mg, 50%). ¹ H-NMR (300 MHz,CDCl₃) δ 4.14 (t, J=5.0 Hz, 2H), 3.09 (s, 3H), 3.06 (q, J=5.0 Hz, 2H),1.50 (s, 9H), 1.46 (s, 9H).

3.3-(3-Methylphenylsulfonyl)amino-6-methyl-1-{[N,N'-di(tert-butoxycarbonyl)][2-(N-methylguanidinooxyethyl)aminocarbonylmethyl]}-2-pyridinone

To a solution of3-(3-methylphenylsulfonyl)amino-6-methyl-1-carboxymethyl-2-pyridinone(253 mg, 0.75 mmol), as prepared in step 2 of Example 5,[N,N'-di(tert-butoxycarbonyl)] 2-aminoethoxy-N-methylguanidine (250 mg,0.75 mmol), as prepared in the preceding step, diisopropylethylamine(180 μL, 1.0 mmol) in N,N-dimethylformamide (10 mL) was added Castro'sreagent (BOP) (355 mg, 0.8 mmol). The mixture was stirred at roomtemperature overnight. Ethyl acetate (50 mL) was added, washed withsaturated NaHCO₃ (2×20 mL), 10% citric acid (2×20 mL) and brine (20 mL),and dried over Na₂ SO₄. After evaporating the solvent in vacuo, theresidue was purified twice by column chromatography (2:1 ethylacetate:hexane; then 2% methanol in methylene chloride) to give thetitle compound as a white solid (380 mg, 78%). ¹ H-NMR (300 MHz, CDCl₃)δ 8.12 (s, 1H), 7.67 (m, 3H), 7.48 (d, J=7.6 Hz, 1H), 7.34 (s, 1H), 7.31(s, 1H), 7.09 (m, 1H), 6.08 (d, J=7.8 Hz, 1H), 4.61 (s, 2H), 4.02 (t,J=5.1 Hz, 2H), 3.46 (q, J=5.3 Hz, 2H), 3.09 (s, 3H), 2.39 (s, 3H), 2.37(s, 3H), 1.53 (s, 9H), 1.47 (s, 9H).

4.3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-N-methylguanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate

A mixture of3-(3-methylphenylsulfonyl)amino-6-methyl-1-{[N,N'-di(tert-butoxycarbonyl)][2-(N-methylguanidinooxypropyl)aminocarbonylmethyl]}-2-pyridinone (370mg, 0.57 mmol), as prepared in the preceding step, and trifluoroaceticacid (2 mL) in methylene chloride (3 mL) was stirred at room temperaturefor 2 h. After evaporating the solvent in vacuo, the residue waspurified by Waters Sep-Pak (10 g, 10% methanol in methylene chloride) togive the title compound as a colorless foam (310 mg, 96%). ¹ H-NMR (300MHz, DMSO-d₆) δ 10.91 (s, 1H), 9.28 (s, 1H), 8.43 (t, J=5.5 Hz, 1H),8.09 (d, J=5.0 Hz, 1H), 7.93 (br s, 2H), 7.66 (s, 1H), 7.62 (m, 1H),7.43 (m, 2H), 7.24 (d, 1H, J=7.6 Hz), 6.09 (d, 1H, J=7.7 Hz), 4.62 (s,2H), 3.79 (t, 2H, J=5.2 Hz), 3.35 (q, 2H, J=5.4 Hz), 2.77 (d, J=4.8 Hz,3H), 2.35 (s, 3H), 2.19 (s, 3H). Mass spectrum (LCMS, ESI) calcd. forC₁₉ H₂₆ SN₆ O₅ : 451.0 (M+H); found: 451.1. MS-MS of 451.1 peak gave394.9 (M--C(═NH)NCH₃).

EXAMPLE 1043-(Benzylsulfonyl)amino-6-methyl-1-[(2-N-methylguanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonetrifluoroacetate ##STR128##

The title compound was prepared in a manner analogous to Example 103. ¹H-NMR (300 MHz, DMSO-d₆) δ 10.89 (s, 1H), 8.57 (s, 1H), 8.47 (t, J=5.5Hz, 1H), 8.09 (br s, 1H), 7.93 (s, 2H), 7.34 (m, 5H), 7.13 (d, J=7.5 Hz,1H), 6.10 (d, J=7.7 Hz, 1H), 4.73 (s, 2H), 4.51 (s, 2H), 3.83 (t, J=5.4Hz, 2H), 3.41 (m, 2H), 2.77 (d, J=4.9 Hz, 3H), 2.25 (s, 3H). Massspectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. forC₁₉ H₂₆ N₆ O₅ S: 451.2 (M+H), 473.2 (M+Na); Found: 451.4, 473.5. MS-MSof 451.4 peak gave 394.9 (M--C(═NH)NCH₃).

EXAMPLE 1053-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-(N-methoxycarbonyl)guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone##STR129##

A suspension of3-(3-methylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonehydrochloride (0.2 g, 0.42 mmol), as prepared in step 5 of Example 5, inacetonitrile (10 mL) was treated with N,N-diisopropylethylamine (0.08mL, 0.46 mmol) and dimethyl pyrocarbonate (0.05 mL, 0.46 mmol). Thereaction mixture was allowed to stir at room temperature overnight. Anadditional solvent, N,N-dimethylformamide (5 mL) was added to effectsolution. Additional dimethyl pyrocarbonate (0.30 mL, 2.76 mmol) wasadded and the reaction mixture was stirred for 2 days. The reactionmixture was evaporated to dryness under high vacuum and the residue waspurified on a silica gel column (5 g SepPak) using 4% methanol inmethylene chloride as eluting solvent to give 0.071 g (29% yield) ofdesired product as a white solid. ¹ H-NMR (300 MHz, DMSO-d₆) δ 9.65 (s,1H), 9.30 (s, 1H), 8.28 (t, J=5.5 Hz, 1H), 7.60-7.67 (m, 2H), 7.38-7.44(m, 2H), 7.23 (d, J=7.5 Hz, 1H), 6.20 (s, 2H), 6.06 (d, J=7.6 Hz, 1H),4.61 (m, 2H), 3.73 (t, J=5.5 Hz, 2H), 3.61 (s, 3H), 3.27-3.31 (m, 2H),2.35 (s, 3H), 2.18 (s, 3H). Mass spectrum (LCMS, ESI) calcd. for C₂₀ H₂₆N₆ O₇ S: 495 (M+H); Found: 495.0.

EXAMPLE 1063-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-(N,N',N"-triethoxycarbonyl)guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone##STR130##

To a solution of3-(3-methylphenyl)sulfonylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonehydrochloride (237 mg, 0.5 mmol), as prepared in step 5 of Example 5,and N,N'-diiso-propylethylamine (180 μL, 1.0 mmol) inN,N-dimethylformamide (10 mL) was added diethyl pyrocarbonate (150 μL,1.0 mmol). The mixture was stirred at ambient temperature overnight. TheN,N-dimethylformamide was evaporated under high vacuum, the residue wasdissolved in methylene chloride (50 mL), washed with 10% citric acid(2×20 mL), brine (20 mL) and dried over Na₂ SO₄. After evaporating thesolvent, the residue was purified by Waters Sep-Pak (10 g, 30-40% ethylacetate in methylene chloride) to give the title compound as a whitesolid (210 mg, 65%). ¹ H-NMR (300 MHz, CDCl₃) δ 9.33 (br s, 1H), 8.64(s, 1H), 8.58 (br s, 1H), 7.97 (m, 2H), 7.52 (d, J=7.5 Hz, 1H), 7.26 (m,2H), 6.15 (d, J=7.7 Hz, 1H), 4.70-5.00 (m, 2H), 4.40 (q, J=7.1 Hz, 2H),4.21 (q, J=7.2 Hz, 2H), 4.07 (q, J=7.1 Hz, 2H), 3.85 (m, 2H), 3.54 (m,2H), 2.41 (s, 3H), 2.39 (s, 3H), 1.41 (t, J=7.1 Hz, 3H), 1.30 (t, J=7.2Hz, 3H), 1.09 (t, J=7.1 Hz, 3H). Mass spectrum (LCMS, ESI) calcd. forC₂₇ H₃₆ N₆ O₁₁ S: 653.0 (M+H); Found: 653.0.

EXAMPLE 1073-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-(N,N'-diethoxycarbonyl)guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone##STR131## and3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-(N-ethoxycarbonyl)guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone##STR132##

To a solution of3-(3-methylphenyl)sulfonylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinonehydrochloride (475 mg, 1.0 mmol), as prepared in step 5 of Example 5,and N-methylmorpholine (220 μL, 2.0 mmol) in N,N'-dimethylformamide (10mL) was added diethyl pyrocarbonate (150 μL, 1.0 mmol). The mixture wasstirred at ambient temperature overnight. The N,N-dimethylformamide wasevaporated under high vacuum, the residue was dissolved in methylenechloride (50 mL), washed with 10% citric acid (2×20 mL), brine (20 mL)and dried over Na₂ SO₄. After evaporating the solvent, the residue waspurified by Waters Sep-Pak (10 g, 30-40% ethyl acetate in methylenechloride then 25 methanol in methylene chloride) to give3-(3-methylphenylsulfonyl)amino-6-methyl-1-[(2-(N,N'-diethoxycarbonyl)guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinoneas a white solid (320 mg, 55%). ¹ H-NMR (300 MHz, CDCl₃) δ 9.34 (br s,1H), 8.74 (s, 1H), 8.59 (br s, 1H), 7.67 (s, 1H), 7.64 (m, 1H), 7.60 (s,1H), 7.38 (d, J=7.5 Hz, 1H), 7.32 (d, J=5.2 Hz, 2H), 6.01 (d, J=7.6 Hz,1H), 4.97+4.67 (m, 2H), 4.40 (q, J=7.1 Hz, 2H), 4.14 (q, J=7.1 Hz, 2H),4.36+3.91 (m, 2H), 3.52 (m, 2H), 2.38 (s, 3H), 2.26 (s, 3H), 1.42 (t,J=7.1 Hz, 3H), 1.21 (t, J=7.1 Hz, 3H). Mass spectrum (LCMS, ESI) calcd.for C₂₄ H₃₂ N₆ O₉ S: 581.2 (M+H); Found: 581.0.3-(3-Methylphenylsulfonyl)amino-6-methyl-1-[(2-(N-ethoxycarbonyl)guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinoneas a white solid (80 mg, 16%). ¹ H-NMR (300 MHz, CDCl₃) δ 8.30 (br s,1H), 8.17 (br s, 1H), 7.56 (m, 4H), 7.33 (m, 2H), 6.14 (d, J=7.7 Hz,1H), 5.77 (br s, 2H), 4.67 (br s, 2H), 4.35 (q, J=7.1 Hz, 2H), 3.85 (m,2H), 3.42 (m, 2H), 2.44 (s, 3H), 2.36 (s, 3H), 1.39 (t, J=7.1 Hz, 3H).Mass spectrum (LCMS, ESI) calcd. for C₂₁ H₂₈ N₆ O₇ S: 509.1 (M+H);Found: 509.1.

EXAMPLE 1083-(3-Methylphenylsulfonyl)amino-6-methyl-1-{[2-N"-(3-phenylpropyl)guanidinooxyethyl]aminocarbonylmethyl}-2-pyridinonehydrochloride ##STR133##

The title compound was prepared in a manner analogous to Example 99. ¹ HNMR (300 MHz, DMSO-d₆) δ 9.25 (s, 1H0, 8.65 (t, 1H, J=5 Hz), 8.03 (br s.3H), 7.78 (br s, 1H), 7.64 (m, 2H), 7.26 (m, 10H), 6.07 (m, 1H), 4.63(br s, 2H), 3.89 (t, 2H, J=4.9 Hz), 3.71 (t, 2H, J=7 Hz), 2.58 (m, 2H),2.34 (s, 3H), 2.16 (s, 3H), 1.87 (m, 2H). Mass spectrum (LCMS, ESI)calcd. for C₂₇ H₃₄ N₆ O₅ S: 555.0 (M+H). Found: 555.1. MS-MS of 555.1peak gave 513.0 (M--C(═NH)NH).

EXAMPLE 109 Tablet Preparation

Tablets containing 25.0, 50.0, and 100.0 mg, respectively, of thefollowing active compounds are prepared as illustrated below:

a.3-benzylsulfonylamino-6-methyl-1-[(3-guanidinooxypropyl)aminocarbonylmethyl]-2-pyridinone;and

b.3-benzylsulfonylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone

TABLET FOR DOSES CONTAINING FROM 25-100 MG OF THE ACTIVE COMPOUND

    ______________________________________                                                      Amount-mg                                                       Active Compound 25.0      50.0    100.00                                      ______________________________________                                        Microcrystalline cellulose                                                                    37.25     100.0   200.0                                       Modified food corn starch                                                                     37.25     4.25    8.5                                         Magnesium stearate                                                                            0.50      0.75    1.5                                         ______________________________________                                    

All of the active compound, cellulose, and a portion of the corn starchare mixed and granulated to 10% corn starch paste. The resultinggranulation is sieved, dried and blended with the remainder of the cornstarch and the magnesium stearate. The resulting granulation is thencompressed into tablets containing 25.0, 50.0, and 100.0 mg,respectively, of active ingredient per tablet.

EXAMPLE 110 Intravenous Solution Preparation

An intravenous dosage form of the above-indicated active compounds isprepared as follows:

    ______________________________________                                        Active Compound        0.5-10.0 mg                                            Sodium Citrate         5-50 mg                                                Citric Acid            1-15 mg                                                Sodium Chloride        1-8 mg                                                 Water for Injection (USP)                                                                            q.s. to 1 ml                                           ______________________________________                                    

Utilizing the above quantities, the active compound is dissolved at roomtemperature in a previously prepared solution of sodium chloride, citricacid, and sodium citrate in Water for Injection (USP, see page 1636 ofUnited States Pharmacopeia/National Formulary for 1995, published byUnited States Pharmacopeial Convention, Inc., Rockville, Md. (1994).

EXAMPLE 111 In vitro Inhibition of Purified Enzymes

Reagents: All buffer salts were obtained from Sigma Chemical Company(St. Louis, Mo.), and were of the highest purity available. The enzymesubstrates, N-benzoyl-Phe-Val-Arg-p-nitroanilide (Sigma B7632),N-benzoyl-Ile-Glu-Gly-Arg-p-nitroanilide hydrochloride (Sigma B2291),N-p-Tosyl-Gly-Pro-Lys-p-nitroanilide (Sigma T6140),N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide (Sigma S7388) andN-CBZ-Val-Gly-Arg-p-nitroanilide (Sigma C7271) were obtained from Sigma.N-succinyl-Ala-Ala-Pro-Arg-p-nitroanilide (BACHEM L-1720) andN-succinyl-Ala-Ala-Pro-Val-p-nitroanilide (BACHEM L-1770) were obtainedfrom BACHEM (King of Prussia, Pa.).

Human α-thrombin, human factor Xa and human plasmin were obtained fromEnzyme Research Laboratories (South Bend, Ind.). Bovine α-chymotrypsin(Sigma C4129), bovine trypsin (Sigma T8642) and human kidney cellurokinase (Sigma U5004) were obtained from Sigma. Human leukocyteelastase was obtained from Elastin Products (Pacific, Mo.).

K_(i) Determinations: All assays are based on the ability of the testcompound to inhibit the enzyme catalyzed hydrolysis of apeptidep-nitroanilide substrate. In a typical K_(i) determination,substrate is prepared in DMSO, and diluted into an assay bufferconsisting of 50 mM HEPES, 200 mM NaCl, pH 7.5. The final concentrationsfor each of the substrates is listed below. In general, substrateconcentrations are lower than the experimentally determined value forK_(m). Test compounds are prepared as a 1.0 mg/ml solution in DMSO.Dilutions are prepared in DMSO yielding 8 final concentrationsencompassing a 200 fold concentration range. Enzyme solutions areprepared at the concentrations listed below in assay buffer.

In a typical K_(i) determination, into each well of a 96 well plate ispipetted 280 mL of substrate solution, 10 mL of test compound solution,and the plate allowed to thermally equilibrate at 37° C. in a MolecularDevices plate reader for >15 minutes. Reactions were initiated by theaddition of a 10 mL aliquot of enzyme and the absorbance increase at 405nm is recorded for 15 minutes. Data corresponding to less than 10% ofthe total substrate hydrolysis were used in the calculations. The ratioof the velocity (rate of change in absorbance as a function of time) fora sample containing no test compound is divided by the velocity of asample containing test compound, and is plotted as a function of testcompound concentration. The data are fit to a linear regression, and thevalue of the slope of the line calculated. The inverse of the slope isthe experimentally determined K_(i) value.

Thrombin: Thrombin activity was assessed as the ability to hydrolyze thesubstrate N-succinyl-Ala-Ala-Pro-Arg-p-nitroanilide. Substrate solutionswere prepared at a concentration of 32 mM (32 mM<<Km=180 mM) in assaybuffer. Final DMSO concentration was 4.3%. Purified human a-thrombin wasdiluted into assay buffer to a concentration of 15 nM. Final reagentconcentrations were: [thrombin]=0.5 nM. [substrateN-succinyl-Ala-Ala-Pro-Arg-p-nitroanilide]=32 mM.

Factor X [FXa]: FXa activity was assessed as the ability to hydrolyzethe substrate N-benzoyl-Ile-Glu-Gly-Arg-p-nitroanilide hydrochloride.Substrate solutions were prepared at a concentration of 51 mM (51<<K_(m)=1.3 mM) in assay buffer. Final DMSO concentration was 4.3%. Purifiedactivated human Factor X was diluted into assay buffer to aconcentration of 300 nM. Final reagent concentrations were: [FXa]=10 nM,[N-benzoyl-Ile-Glu-Gly-Arg-p-nitroanilide hydrochloride]=51 mM.

Plasmin: Plasmin activity was assessed as the ability to hydrolyze theN-p-Tosyl-Gly-Pro-Lys-p-nitroanilide. Substrate solutions were preparedat a concentration of 37 mM (37 mM<<K_(m) =243 mM) in assay buffer.Final DMSO concentration was 4.3%. Purified human plasmin was dilutedinto assay buffer to a concentration of 240 nM. Final reagentconcentrations were: [Plasmin]=8 nM,[N-p-Tosyl-Gly-Pro-Lys-p-nitroanilide]=37 mM.

Chymotrypsin: Chymotrypsin activity was assessed as the ability tohydrolyze N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide. Substrate solutionswere prepared at a concentration of 14 mM (14 mM<<K_(m) =62 mM) in assaybuffer. Final DMSO concentration was 4.3%. Purified bovine chymotrypsinwas diluted into assay buffer to a concentration of 81 nM. Final reagentconcentrations were: [Chymotrypsin]=2.7 nM,[N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide]=14 mM.

Trypsin: Trypsin activity was assessed as the ability to hydrolyzeN-benzoyl-Phe-Val-Arg-p-nitroanilide. Substrate solutions were preparedat a concentration of 13 mM (13 mM<<K_(m) =291 mM) in assay buffer.Final DMSO concentration was 4.3%. Purified bovine trypsin was dilutedinto assay buffer to a concentration of 120 nM. Final reagentconcentrations were: [Trypsin]=4 nM,[N-benzoyl-Phe-Val-Arg-p-nitroanilide]=13 mM.

Elastase: Elastase activity was assessed as the ability to hydrolyzeN-succinyl-Ala-Ala-Pro-Val-p-nitroanilide. Substrate solutions wereprepared at a concentration of 19 mM (19 mM<<K_(m) =89 mM) in assaybuffer. Final DMSO concentration was 4.3%. Purified human leukocyteelastase was diluted into assay buffer to a concentration of 750 nM.Final reagent concentrations were: [Elastase]=25 nM,[-succinyl-Ala-Ala-Pro-Val-p-nitroanilide]=19 mM.

Urokinase: Urokinase activity was assessed as the ability to hydrolyzeN-CBZ-Val-Gly-Arg-p-nitroanilide. Substrate solutions were prepared at aconcentration of 100 mM (100 mM<K_(m) =1.2 mM) in assay buffer. FinalDMSO concentration was 4.3%. Purified human kidney urokinase was dilutedinto assay buffer to a concentration of 1.2 mM. Final reagentconcentrations were: [Urokinase]=40 nM, and[N-CBZ-Val-Gly-Arg-p-nitroanilide]=100 mM.

The results of compounds of the invention are shown in the followingtable.

                  TABLE 1                                                         ______________________________________                                        Assay, K.sub.i (nM) or (% Inhibition at (nM))                                 Eg.  Throm-                                                                   No.  bin     FXa     Chymo. Elastase                                                                             Plasmin                                                                              Trypsin                             ______________________________________                                        1    53      0@      0@24,000                                                                             0@24,000                                                                             0@24,000                                                                             0@24,000                                         24,000                                                           2    7.9     24,000  14,000 0@24,500                                                                             0@24,500                                                                             0@24,500                            4    29      7,900          0@79,000                                          5    6.0             0@24,600                                                                             0@24,600                                                                             0@24,600                                                                             0@24,600                            8    43                     0@56,000      0@56,000                            16   2.0     2,200          0@19,000      4,000                               24   2.0     2,200          0@18,000      7,600                               30   61      7.600   0@23,500                                                                             0@23,500                                                                             0@23,500                                                                             0@23,500                            38   51      420     0@20,000                                                                             0@20,000                                                                             0@20,000                                                                             0@20,000                            55   220     2,100                        2,300                               71   580     8,700   0@12,000                                                                             0@12,000                                                                             0@12,000                                                                             0@12,000                            85   290     1,300   0@18,000                                                                             0@18,000                                                                             0@18,000                                                                             1,600                               ______________________________________                                         Chymo. = chymotrypsin                                                    

The results indicate that the compounds of the present invention arepotent and highly selective inhibitors of thrombin.

Having now fully described this invention, it will be understood tothose of ordinary skill in the art that the same can be performed withina wide and equivalent range of conditions, formulations, and otherparameters without affecting the scope of the invention or anyembodiment thereof. All patents and publications cited herein are fullyincorporated by reference herein in their entirety.

What is claimed is:
 1. A compound having the Formula VII: ##STR134## ora solvate, hydrate or pharmaceutically acceptable salt thereof;wherein:R¹ is alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl,aryl, aralkyl, heterocycle or heterocycloalkyl, any of which may beoptionally substituted; Z is --SO₂ --, or a covalent bond; Het is##STR135## where R³, R⁴ and R⁵ are independently hydrogen, alkyl,cycloalkyl, alklenyl, alkynyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted heteroaryl, trifluoromethyl,halogen, hydroxyalkyl, cyano, nitro, carboxamido, alkoxycarbonylmethyl,carboxymethyl, --CO₂ R^(x), --CH₂ OR^(x) or --OR^(x), where R^(x), ineach instance, is independently one of hydrogen, alkyl or cycloalkylwherein said alkyl or cycloalkyl groups may optionally have one or moreunsaturations; R⁷ is hydrogen, C₁₋₄ alkyl, or C₂₋₄ alkenyl; R⁸ ishydrogen, alkyl, alkenyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl,monoalkylamino (C₂₋₁₀)alkyl, dialkylamino(C₂₋₁₀)alkyl or carboxyalkyl;R¹², R¹³, R¹⁴ and R¹⁵ are independently hydrogen, alkyl, aralkyl, aryl,hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl orcarboxyalkyl;or R¹² and R¹³ are taken together to form --(CH₂)_(y) --,where y is 2 to 7, while R¹⁴ and R¹⁵ are defined as above; or R¹⁴ andR¹⁵ are taken together to form --(CH₂)_(q) --, where q is 2 to 7,whileR¹² and R¹³ are defined as above; or R¹² and R¹⁴ are taken together toform --(CH₂)_(r) --, where r is 0 (a bond) or 1 to 7, while R¹³ and R¹⁵are defined as above; X is oxygen or NR⁹,where R⁹ is hydrogen, alkyl,cycloalkyl or aryl, wherein said alkyl, cycloalkyl or aryl can beoptionally substituted with amino, monoalkylamino, dialkylamino, alkoxy,hydroxy, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,aryl, heteroaryl, acylamino, cyano or trifluoromethyl; R^(a), R^(b) andR^(c) are independently hydrogen, alkyl, hydroxy, alkoxy, aryloxy,aralkoxy, alkoxycarbonyloxy, cyano or --CO₂ R^(w), whereR^(w) is alkyl,cycloalkyl, phenyl, benzyl, ##STR136## where R^(d) and R^(e) areindependently hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl or phenyl, R^(f) ishydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl or phenyl, R^(g) is hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl or phenyl, and R^(b) is aralkyl or C₁₋₆ alkyl; n isfrom zero to 8; and m is from zero to
 6. 2. A compound of claim 1,wherein R¹ is C₆₋₁₀ ar(C₁₋₄) alkyl, C₆₋₁₀ aryl, C₄₋₇cycloalkyl(C₁₋₄)alkyl, heterocycle or heterocyclo(C₁₋₄)alkyl, any ofwhich is optionally substituted; and wherein the heterocycle of saidheterocycle or heterocyclo(C₁₋₄)alkyl is a 5- to 7-member mono-cyclic,or 9- to 10-member bi-cyclic heterocyclic ring that is saturated orunsaturated, and contains 1 to 3 heteroatoms selected from N, O and S.3. A compound of claim 2, wherein R¹ is C₆₋₁₀ ar(C₁₋₄) alkyl, C₆₋₁₀aryl, C₄₋₇ cycloalkyl(C₁₋₄)alkyl, any of which is optionally substitutedby 1-5 of hydroxy, nitro, trifluoromethyl, halogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₆₋₁₀ aryl, C₁₋₆ alkoxy, C₆₋₁₀ ar(C₁₋₆)alkoxy, C₁₋₆ aminoalkyl,C₁₋₆ aminoalkoxy, amino, mono(C₁₋₄)alkylamino di(C₁₋₄)alkylamino, C₂₋₆alkylcarbonylamino, C₂₋₆ alkoxycarbonylamino, C₂₋₆ alkoxycarbonyl,carboxy, C₁₋₆ hydroxyalkyl, C₂₋₆ hydroxyalkoxy,(C₁₋₆)alkoxy(C₂₋₆)alkoxy, mono- and di-C₁₋₄ alkylamino (C₂₋₆)alkoxy,C₂₋₁₀ mono(carboxyalkyl)amino, bis(C₂₋₁₀ carboxyalkyl) amino, C₆₋₁₄ar(C₁₋₆) alkoxycarbonyl, C₂₋₆ alkynylcarbonyl, C₁₋₆ alkylsulfonyl, C₂₋₆alkenylsulfonyl, C₂₋₆ alkynylsulfonyl, C₆₋₁₀ arylsulfonyl, C₆₋₁₀ar(C₁₋₆) alkylsulfonyl, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonamido, C₆₋₁₀arylsulfonamido, C₆₋₁₀ ar(C₁₋₆) alkylsulfonamido, amidino, guanidino,C₁₋₆ alkyliminoamino, formyliminoamino, C₂₋₆ carboxyalkoxy, C₂₋₆carboxyalkyl, carboxyalkylamino, cyano, trifluoromethoxy, orperfluoroethoxy.
 4. A compound of claim 1, wherein Het is: ##STR137##where R³, R⁴ and R⁵ are independently hydrogen, C₁₋₄ alkyl, C₃₋₇cycloalkyl, C₆₋₁₄ aryl, C₆₋₁₀ ar(C₁₋₄)alkyl, trifluoromethyl, halogen,hydroxyalkyl, cyano, nitro, carboxamido, carboxy, alkoxycarbonyl,carboxymethyl, alkoxycarbonylmethyl, alkoxy, hydroxy, orcycloalkyloxycarbonyl.
 5. A compound of claim 4, wherein R³, R⁴ and R⁵are independently hydrogen, methyl, ethyl, propyl, chloro, bromo,trifluoromethyl, hydroxymethyl, methoxy, ethoxy, carboxamido, nitro,phenyl, cyclopropyl, hydroxy, isopropyl, methoxycarbonyl, ethoxycarbonyland benzyl.
 6. A compound of claim 1, wherein R³ and R⁴ groups areindependently hydrogen, C₁₋₁₂ alkyl, or C₂₋₆ alkenyl.
 7. A compound ofclaim 6, wherein R³ and R⁴ are hydrogen.
 8. A compound of claim 1,wherein R⁵ is hydrogen, halogen, C₁₋₅ alkyl, C₃₋₆ alkenyl, C₃₋₅cycloalkyl, trifluoromethyl, or C₁₋₄ alkoxy.
 9. A compound of claim 1,wherein Het is: ##STR138## wherein R³ and R⁴ are independently selectedto be hydrogen or methyl, andR⁵ is selected from the group consisting ofhydrogen, methyl, ethyl, propenyl, allyl, propyl, isopropyl, butyl,R-sec-butyl, S-sec-butyl, isobutyl, 1-pentyl, R-2-pentyl, S-2-pentyl,3-pentyl, S-1-(2-methyl)-butyl, R-2-(3-methyl)-butyl,1-(3-methyl)-butyl, R-1-(2-methyl)-butyl, cyclopentyl, 2-pyrrolyl,3-pyrrolyl, 1-hexyl, S-2-hexyl, R-2-hexyl, R-3-hexyl, and S-3-hexyl. 10.A compound of claim 9, wherein R⁵ is hydrogen, methyl, ethyl, propyl orisopropyl.
 11. A compound of claim 1, wherein Z is --SO₂ -- or acovalent bond.
 12. A compound of claim 1, wherein R⁷ is hydrogen.
 13. Acompound of claim 1, wherein X is oxygen.
 14. A compound of claim 1,wherein X is NR⁹.
 15. A compound of claim 1, wherein R⁹ is hydrogen orC₁₋₆ alkyl, optionally substituted by one, two or three, preferably one,of amino, monoalkylamino, dialkylamino, alkoxy, hydroxy, alkoxycarbonyl,aryloxycarbonyl, aralkoxycarbonyl, carboalkoxy, phenyl, cyano,trifluoromethyl, acetylamino, pyridyl, thiophenyl, furyl, pyrrolyl orimidazolyl.
 16. A compound of claim 1, wherein R⁹ is hydrogen, methyl,ethyl, propyl, n-butyl, benzyl, phenethyl, 2-hydroxyethyl,3-hydroxypropyl, 4-hydroxybutyl, carboxymethyl or carboxyethyl.
 17. Acompound of claim 1, wherein R⁸ is hydrogen, C₁₋₆ alkyl or C₆₋₁₀ aryl(C₁₋₆)alkyl.
 18. A compound of claim 1, whereinR¹², R¹³, R¹⁴ and R¹⁵ areindependently one of hydrogen, C₁₋₆ alkyl, C₆₋₁₀ ar(C₁₋₆)alkyl, C₆₋₁₀aryl, C₂₋₁₀ hydroxyalkyl or C₂₋₇ carboxyalkyl.
 19. A compound of claim18, whereinR¹², R¹³, R¹⁴ and R¹⁵ are independently hydrogen, methyl,ethyl, propyl, n-butyl, benzyl, phenylethyl, 2-hydroxyethyl,3-hydroxypropyl, 4-hydroxybutyl, 2-carboxymethyl, 3-carboxyethyl and4-carboxypropyl.
 20. A compound of claim 1, whereinR^(a), R^(b) andR^(c) are independently hydrogen, hydroxy, C₁₋₆ alkyl, C₁₋₆ alkoxy,cyano or --CO₂ R^(w), where R^(w), in each instance, is preferably oneof C₁₋₄ alkyl, C₄₋₇ cycloalkyl or benzyl, ##STR139## where R^(d), R^(e)and R^(g) are hydrogen, R^(f) is methyl, and R^(h) is benzyl ortert-butyl.
 21. A compound of claim 20, whereinR^(a), R^(b) and R^(c)are hydrogen, methyl, ethyl, propyl, n-butyl, hydroxy, methoxy, ethoxy,cyano, --CO₂ CH₃, --CO₂ CH₂ CH₃ and --CO₂ CH₂ CH₂ CH₃.
 22. A compound ofclaim 21, wherein R^(a), R^(b) and R^(c) are each hydrogen.
 23. Acompound of claim 1, wherein n is zero to 6, and m is zero to
 4. 24. Acompound of claim 23, wherein n is zero to 4 and m is zero, 1 or
 2. 25.A compound of claim 1, wherein:R¹ is C₆₋₁₀ ar(C₁₋₄) alkyl, C₆₋₁₀ aryl,C₄₋₇ cycloalkyl(C₁₋₄)alkyl, any of which is optionally substituted by1-5 of hydroxy, nitro, trifluoromethyl, halogen, C₁₋₆ alkyl, C₆₋₁₀ aryl,C₁₋₆ alkoxy, C₆₋₁₀ ar(C₁₋₆)alkoxy, C₁₋₆ aminoalkyl, C₁₋₆ aminoalkoxy,amino, mono(C₁₋₄)alkylamino, di(C₁₋₄)alkylamino, C₂₋₆alkoxycarbonylamino, C₂₋₆ alkoxycarbonyl, carboxy, C₁₋₆ hydroxyalkyl,C₂₋₆ hydroxyalkoxy, (C₁₋₆)alkoxy(C₂₋₆)alkoxy, mono- and di-C₁₋₄alkylamino (C₂₋₆)alkoxy, C₂₋₁₀ mono(carboxyalkyl)amino, bis(C₂₋₁₀carboxyalkyl) amino, C₆₋₁₄ ar(C₁₋₆) alkoxycarbonyl, C₂₋₆alkynylcarbonyl, C₁₋₆ alkylsulfonyl, C₂₋₆ alkenylsulfonyl, C₂₋₆alkynylsulfonyl, C₆₋₁₀ arylsulfonyl, C₆₋₁₀ ar(C₁₋₆) alkylsulfonyl, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonamido, C₆₋₁₀ arylsulfonamido, C₆₋₁₀ar(C₁₋₆) alkylsulfonamido, amidino, guanidino, C₁₋₆ alkyliminoamino,formyliminoamino, C₂₋₆ carboxyalkoxy, C₂₋₆ carboxyalkyl,carboxyalkylamino, cyano, trifluoromethoxy, or perfluoroethoxy; Het is:##STR140## wherein R³ and R⁴ are independently selected to be hydrogenor methyl, and R⁵ is selected from the group consisting of hydrogen,methyl, ethyl, propenyl, allyl, propyl, isopropyl, butyl, R-sec-butyl,S-sec-butyl, isobutyl, 1-pentyl, R-2-pentyl, S-2-pentyl, 3-pentyl,S-1-(2-methyl)-butyl, R-2-(3-methyl)-butyl, 1-(3-methyl)-butyl,R-1-(2-methyl)-butyl, cyclopentyl, 2-pyrolyl, ³ -pyrolyl, 1-hexyl,S-2-hexyl, R-2-hexyl, R-3-hexyl, and S-3-hexyl; Z is --SO₂ -- or acovalent bond; R¹², R¹³, R¹⁴ and R¹⁵ are independently one of hydrogen,C₁₋₆ alkyl, C₆₋₁₀ ar(C₁₋₆)alkyl, C₆₋₁₀ aryl, C₂₋₁₀ hydroxyalkyl or C₂₋₇carboxyalkyl; X is oxygen; R⁸ is hydrogen, C₁₋₄ alkyl or C₆₋₁₀ aryl(C₁₋₆)alkyl; R^(a), R^(b) and R^(c) are hydrogen, methyl, ethyl, propyl,n-butyl, hydroxy, methoxy, ethoxy, cyano, --CO₂ CH₃, --CO₂ CH₂ CH₃ and--CO₂ CH₂ CH₂ CH₃ ; n is zero to 6, and m is zero to
 4. 26. A compoundof claim 1, whereinZ is --SO₂ --, R¹ is substituted or unsubstitutedaryl or aralkyl, Het is ##STR141## X is O, R⁸ is hydrogen, C₁₋₄ alkyl orC₆₋₁₀ aryl(C₁₋₆)alkyl, and R^(a), R^(b) and R^(c) are all hydrogen. 27.A compound of claim 26, whereinR¹ is substituted or unsubstituted benzylor phenyl.
 28. A compound having Formula VIII: ##STR142## or a solvate,hydrate of pharmaceutically acceptable salt thereof; wherein Z' is --SO₂--, or a covalent bond;R²¹ is:R²² (CH₂)_(k), where k is 0-4,(R²²)(OR²²)CH(CH₂)_(p), where p is 1-4, (R²²)₂ CH(CH₂)_(k), where k is0-4 and R²² can be the same or different, and wherein (R²²)₂ can also bea ring substituent on CH represented by C₃₋₇ cycloalkyl, C₇₋₁₂ bicyclicalkyl, or a 5- to 7-membered mono- or 9- to 10-membered bicyclicheterocyclic ring which can be saturated or unsaturated, and whichcontains from one to three heteroatoms selected from the groupconsisting of N, O and S, and R²² O(CH₂)_(p), wherein p is 1-4; R²² ishydrogen; phenyl, unsubstituted or substituted with one or more of C₁₋₄alkyl, C₁₋₄ alkoxy, halogen, trifluoromethyl, hydroxy, COOH, or CONH₂ ;naphthyl; biphenyl; a 5- to 7-membered mono- or a 9- to 10-memberedbicyclic heterocyclic ring which can be saturated or unsaturated, andwhich contains from one to three heteroatoms selected from the groupconsisting of N, O and S; C₁₋₄ alky; C₃₋₇ cycloalkyl, or C₇₋₁₂ bicyclicalkyl; R²⁵ is hydrogen; C₁₋₄ alkyl; C₃₋₇ cycloalkyl, or trifluoromethyl;R^(a), R^(b) and R^(c) are independently hydrogen, hydroxy, or cyano;R³², R³³, R³⁴ and R³⁵ are independently one of hydrogen, C₁₋₆ alkyl,C₂₋₁₀ carboxyalkyl or C₂₋₁₀ hydroxyalkyl, or R³² and R³³ are takentogether to form --(CH₂)_(y) --, where y is 2 to 5, while R³⁴ and R³⁵are defined as above; or R³⁴ and R³⁵ are taken together to form--(CH₂)_(q) --, where q is 2 to 5, while R³² and R³³ are defined asabove; or R³² and R³⁴ are taken together to form --(CH₂)_(r) --, where ris 0 (a bond) or 1-4, while R³³ and R³⁵ are defined as above; R²⁸ ishydrogen, C₁₋₄ alkyl or C₆₋₁₀ aryl (C₁₋₄)alkyl; X' is O; n is from zeroto 4; and m is zero to
 2. 29. A compound of claim 28, wherein Z' is--SO₂ --.
 30. A compound of claim 28, wherein R²¹ is R²² (CH₂)_(k),(R²²)₂ CH(CH₂)_(k), phenyl, or (phenyl)₂ --CH.
 31. A compound of claim28, wherein R²⁵ is C₁₋₄ alkyl.
 32. A compound of claim 3 1, wherein R²⁵is methyl.
 33. A compound of claim 28, wherein R²⁸ is hydrogen, C₁₋₄alkyl, or benzyl.
 34. A compound of claim 1, whereinR¹ is phenyl,benzyl, 1-naphtylmethyl, 2-naphthylmethyl, pyridyl, pyridylmethyl,quinolinyl or quinolinylmethyl, any of which is optionally substitutedby 1-5 of chloro, methoxy, methyl, trifluoromethyl, cyano, nitro,methylsulfonyl, amino or dimethylamino.
 35. A compound of claim 1,whereinR¹ is 8-quinolinyl, 5-methyl-8-quinolinyl, 8-quinolinylmethyl,5-methyl-8-quinolinylmethyl, 4-benzo-2,1,3-thiadiazolyl,5-chloro-2-thiophenyl, 5-chloro-1,3-dimethyl-4-pyrazolyl, pyridyl,isoquinolinyl, pyridylmethyl, isoquinolinylmethyl, tetrahydroquinolinyland tetrahydroquinolinylmethyl.
 36. A compound of claim 1, wherein m andn are each zero and R¹², R¹³, R¹⁴ and R¹⁵ are each hydrogen.
 37. Acompound of claim 1, which is oneof:3-benzylsulfonylamino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(3-methylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-benzylsulfonylamino-6-methyl-1-[2-guanidinooxymethyl)cyclopropyl)amninocarbonylmethyl]-2-pyridinone;3-(3-chlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(2-iodobenzylsulfonyl)amino-6-methyl-2-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(2-chlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)amninocarbonylmethyl]-2-pyridinone;3-(2-bromobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)amninocarbonylmethyl]-2-pyridinone;3-(3-fluorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(4-chlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)-amnocarbonylmethyl]-2-pyridinone;3-(2-chloro-6-fluorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(2-fluorobenzylsulfonlyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(4-fluorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(2,3-dichlorobenzylsulfonyl)amino-6-methyl-1-[2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(3,4-difluorobenzylsulfonyl)amino-6-methyl-1-[2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(2,4-dichlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(2,5-dichlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(3,4-dichlorobenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(1-naphthalenylmethylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(2-methylbenzylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-phenysulfonylanino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(3-chlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(4-methoxyphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(3,4-dichlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(3-bromophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(3,4-dichlorophenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(4-methylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(4-ethylphenylsulfonyl)amino-6-methyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(3-methylphenylsulfonyl)amino-6-isopropyl-1-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(3-methylphenylsulfonyl)amino-6-ethyl-1-[2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone,3-(3-methylphenylsulfonyl)amino-6-propyl-[(2-guanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(3-methylphenylsulfonyl)amino-6-methyl-1-[(2-N"-methylguanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(3-methylphenylsulfonyl)amino-6-methyl-1-[2-N"-butylguanidinooxyethyl)aminocarbonylmethyl]-2-pyridinone;3-(3-methylphenylsulfonyl)amino-6-methyl-1-{[2-N"-(3-phenylpropyl)guanidinooxyethyl]aminocarbonylmethyl}-2-pyridinone;andpharmaceutically acceptable salts thereof.